Muco-adhesive, controlled release formulations of levodopa and/or esters of levodopa and uses thereof

ABSTRACT

The invention provides an oral solid formulation comprising (a) a controlled release component comprising a core comprising levodopa, wherein the core is coated with a layer of a muco-adhesive polymer and externally coated with a layer of an enteric polymer; and (b) an immediate release component comprising carbidopa and levodopa.

This application is a continuation of U.S. patent application Ser. No.17/148,320 filed on Jan. 13, 2021, which is a continuation of U.S.patent application Ser. No. 16/573,634 filed on Sep. 17, 2019, now U.S.Pat. No. 10,987,313, which is a continuation-in-part of U.S. patentapplication Ser. No. 16/360,936 filed on Mar. 21, 2019, now U.S. Pat.No. 10,688,058, which is a continuation of U.S. patent application Ser.No. 15/092,086 filed on Apr. 6, 2016, now U.S. Pat. No. 10,292,935,which is a continuation-in-part application of PCT Application No.PCT/US2014/059554 filed Oct. 7, 2014, which claims the benefit of U.S.Ser. No. 61/887,762 filed on Oct. 7, 2013, the contents of all arehereby incorporated by reference in their entireties into the presentapplication.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains.

FIELD OF THE INVENTION

The present invention relates to controlled release pharmaceuticalcompositions of levodopa (LD) and esters of LD or salts thereof,formulated with a muco-adhesive material and an enteric material and,optionally, with a rate-controlling material, to yield enhanced drugdelivery attributes. These formulations are useful for the treatment ofconditions such as neurological diseases associated with reduced orimpaired dopamine levels. The formulations are also useful in treatingpatients with Parkinson's disease (hereinafter “PD”).

BACKGROUND OF THE INVENTION

Patients suffering from PD frequently have periods in which theirmobility becomes difficult, often resulting in an inability to move.Abnormally low levels of dopamine, a neurotransmitter that affectsmobility and control of the skeletal-muscular system, is commonlybelieved to be the main cause of these motor symptoms in PD patients.However, administration of dopamine is not effective to treat the motorsymptoms of Parkinson's disease because dopamine does not cross theblood-brain barrier. To resolve this problem, PD patients areadministered LD, the metabolic precursor of dopamine, but LD is notwithout its issues.

Over time patients treated with LD exhibit symptoms of “wearing off,”where a single dose of LD no longer lasts as long as in the early daysof LD therapy (usually 5-10 years after start of LD therapy). Suchpatients may develop motor fluctuations characterized by end-of-dosefailure, peak dose dyskinesia, and akinesia. The advanced form of motorfluctuations (also commonly referred to as the ‘on-off’ phenomenon) ischaracterized by unpredictable swings from mobility to immobility.Although the causes of these motor fluctuations are not completelyunderstood, advanced patients generally benefit from treatment regimensthat produce steady plasma levels of LD, such as through intestinalinfusion of LD as such delivery method may mimic normally tonicendogenous dopamine. However, intestinal infusion of LD is restrictive,invasive and cumbersome. Oral delivery of LD is preferred, but plasmaconcentration levels remain difficult to control via oral delivery.

Combinations of LD and a decarboxylase inhibitor (typically carbidopa(CD)) to treat PD are known in the pharmaceutical arts. Currently,several formulations containing a combination of LD and CD arecommercially available, e.g., SINEMET®, SINEMET® CR, STALEVO®, PARCOPA®,RYTARY® and their corresponding generic products. In addition, adecarboxylase inhibitor approved for use outside of the United States,is benserazide, which may be given in combination with LD.

Nonetheless, a need remains for an oral LD formulation that providessteadier plasma concentrations of LD with minimal ‘peak-to-trough’fluctuations during daily dosing and that yields a longerduration-of-effect than the commercially available oral dosage forms ofLD. In addition, it is desirable for an oral LD formulation to providetherapeutic blood levels of LD quickly, thereby providing a rapid “on”to a PD patient in need thereof.

SUMMARY OF THE INVENTION

The current invention provides controlled release/extended absorptionoral dosage forms comprising LD and/or an ester of LD or salts thereoffor treatment of PD and other dopamine deficiency disorders. Morespecifically, in some embodiments, the dosage form comprises at leasttwo components: (i) a first component or immediate release componentthat provides immediate release of LD and/or an ester of LD or saltsthereof; and (ii) a second component or controlled release componentthat provides for a controlled or sustained release of LD and/or anester of LD or salts thereof. In certain embodiments, the secondcomponent or controlled release component comprises a core containing LDand/or an ester of LD or salts thereof that is mixed, coated or layeredwith a muco-adhesive material, preferably a muco-adhesive polymer andexternally coated with an enteric material, preferably an entericpolymer. The second component or controlled release component may alsocontain a rate controlling material that will contribute to thecontrolled release of the LD and/or an ester of LD or salts thereof. Therate controlling material may be part of the controlled releasecomponent. For example, the rate controlling material may be a ratecontrolling polymer applied to the drug containing core and as anundercoating to a coating or layer containing a muco-adhesive materialor the rate controlling material may mixed with the LD and/or an esterof LD or salts thereof to form a controlled release matrix or controlledrelease core of the controlled release component. The second orcontrolled release component is essential to provide extendedabsorption, thereby providing prolonged and steady therapeutic coverage.

The oral dosage forms of the present invention may also comprise adecarboxylase inhibitor, such as CD. The decarboxylase inhibitor, suchas CD, may be present in the first or immediate release LD component,the second or controlled release LD component or in both the first orimmediate release LD component and second or controlled release LDcomponent. The decarboxylase inhibitor, such as CD, may also be presentin a component that is separate and distinct from the first or immediaterelease LD component and/or the second or controlled release LDcomponent. More specifically, one embodiment of the controlled releaseextended absorption oral dosage form of the present invention maycomprise: (i) a first or immediate release component comprising LD; and(ii) a second or controlled release component comprising LD. Anotherembodiment may comprise: (i) a first or immediate release componentcomprising LD and CD; and (ii) a second or controlled release componentcomprising LD. A further embodiment may comprise: (i) a first orimmediate release component comprising LD; and (ii) a second orcontrolled release component comprising LD and CD. A still furtherembodiment may comprise: (i) a first or immediate release componentcomprising LD and CD; and (ii) a second or controlled release componentcomprising LD and CD. Another embodiment may comprise (i) a first orimmediate release component comprising LD; and (ii) a second orcontrolled release component comprising LD. (iii) a third or immediaterelease component comprising CD; and/or (iv) a fourth or controlledrelease component comprising CD.

The first, second, third and/or forth components may be separate anddistinct components or may be combined to form distinct parts or regionsof a larger combined component. For example, the first or immediaterelease component may comprise a powder or granules comprising LD and/orCD and optionally one or more pharmaceutically acceptable excipients andthe powder or granules are a separate and distinct composition from thesecond or controlled release component however both may be incorporatedinto a capsule for administration to a patient. Alternatively, the firstor immediate release component may comprise a coating or layercomprising LD and/or CD and optionally one or more pharmaceuticallyacceptable excipients wherein the coating or layer is applied to or partof the second or controlled release component. In this alternativeembodiment, the first or immediate release component is combined withthe second or controlled release component to form a distinct part orcomponent of the larger combined component. It will be appreciated bythe skilled artisan that the location, structure and/or placement of thefirst or immediate release component with respect to the second orcontrolled release components in the final dosage form is not criticalprovided the first or immediate release component allows for theimmediate release of the drug such as LD and/or CD followingadministration of the dosage form to a patient and the second orcontrolled release component has the muco-adhesive and modified releaseproperties described herein.

The controlled release/extended absorption oral dosage forms of thepresent invention are useful in treating patients with reduced orimpaired dopamine levels, including but not limited to patients with PD.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the schematic configuration of the enteric-coated,muco-adhesive controlled release multi-particulates of this invention.

FIG. 2 is a line graph showing the in vitro dissolution profiles ofIPX203 multi-particulate 10 formulations IPX203-C0004, IPX203-C0005 andIPX203-C0006.

FIG. 3 shows the plasma profile for IPX203 multi-particulateformulations IPX203-C0004, IPX203-C0005 and IPX203-C0006 in comparisonwith Sinemet® CR.

FIG. 4 are line graphs showing in vitro release profiles of testregimens A-D for IPX203-B13-01.

FIG. 5 is a line graph showing in vivo levodopa plasma profiles ofIPX203 formulations that provide plasma profiles with levodopa levelsmaintained at or greater than ½ C_(max) longer than about 6 hours underfasted conditions.

FIG. 6 shows in vitro release profiles of IPX203-C0023, -C0024, -C0025and -C0026 formulations.

FIG. 7 shows in vivo levodopa plasma profiles for the formulationstested in IPX203-B14-01 PK study under fasted conditions.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the present disclosure belongs. As used herein thefollowing terms have the following meanings:

As used herein, the term “about” when used before a numericaldesignation, e.g., temperature, time, amount, concentration, and suchother, including a range, indicates approximations which may vary by (+)or (−) 10%, 5% or 1%.

As used herein the term “component” is used in its broadest conventionalinterpretation unless dictated by context or specifically stated. Morespecifically, a component may be an element, a constituent part, asingle ingredient or a mixture of ingredients. For example, an immediaterelease component may include a single ingredient such as a drug itselfor it may be a combination of a drug and one or more pharmaceuticallyacceptable excipients provided the “immediate release component” willrelease the drug immediately upon administration.

It must be noted that as used herein and in the appended claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “aformulation” includes a plurality of compounds.

Compositions of the Invention

The invention provides controlled release oral solid formulations of LDand/or an ester of LD or a salt thereof providing a relatively steady LDplasma or serum concentration profile over a prolonged period of timeand enhancing absorption of the active agents in the gastrointestinaltract of a subject. Without being limited by any one theory, it isbelieved that the outer enteric coating of the controlled releasecomponent will delay release of the active agents or drugs from thecontrolled release component until the controlled release component haspassed through the patient's stomach and into the small intestine. Inthe small intestine, the outer enteric coating will dissolve and exposethe inner muco-adhesive material that facilitates adhesion of thecontrolled release component to the intestinal mucosa, therebyprolonging or delaying passage of the controlled release componentthrough the intestine and improving absorption. It is desirable toretain the controlled release component within the small intestine,preferably the upper regions of the small intestine, where LD isabsorbed most efficiently.

In some embodiments, the controlled release component comprises a ratecontrolling material, which may be the same or different from themuco-adhesive material. The rate controlling material and/or themuco-adhesive material slows or prolongs the release of active agent(s)or drug(s) from the controlled release component, thereby furtherextending the release and absorption of drug(s), preferably LD andoptionally CD. The controlled release component should release thedrug(s) such as LD or CD over a four to ten hour period preferably afive to eight hour period.

The immediate release component should provide fast release of thedrug(s) such as LD and CD and thereby a rapid absorption of the drug(s)such as LD and CD. The rapid absorption is important for PD patients inneed of a fast “on.” As a result, dosage forms of the present inventioncan provide LD plasma levels that rise quickly, preferably totherapeutic levels, and extend for a prolonged period of time.

In certain embodiments the amount of immediate release LD, and/or itsesters or salts thereof should range from about 10% to about 40% basedon the total amount of LD and/or its esters or salts thereof in the oraldosage forms, preferably about 15% to 35%, and most preferably about20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28% 29% or 30%.

Decarboxylase inhibitors such as CD are often provided with LDformulations in order to inhibit decarboxylation of LD, therebyincreasing the LD bioavailability. In the dosage forms of the presentinvention, a decarboxylase inhibitor may be included in the immediaterelease component, the controlled release component, both the immediaterelease and controlled release component or in separate immediaterelease and/or controlled release components as described previously.Preferably, the decarboxylase inhibitor is CD and is included only in animmediate release form such as in the immediate release component withthe LD or in a separate immediate release component from the LD. Inalternative embodiments, the decarboxylase inhibitor, preferably CD, isincluded in both an immediate release form as previously described and acontrolled release form such as in the controlled release component withthe LD or in a separate controlled release component that does notcontain LD. In the various embodiments the amount of immediate releasedecarboxylase inhibitor, preferably CD, should range from about 75% toabout 100% based on the total amount of decarboxylase inhibitor in theoral dosage forms, preferably about 80% to 100%, and most preferablyabout 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99% or 100%.

In one embodiment of the invention, the oral dosage forms comprise (1)one or more controlled release components comprising LD and/or an esterof LD or salts thereof and (2) one or more immediate release componentscomprising LD and/or an ester of LD or salts thereof. The one or morecontrolled release components may be formulated as a tablet,mini-tablet, bead, pellet, granule or combination thereof. Thecontrolled release components may comprise a core containing LD and/oran ester of LD or salts thereof coated with a layer comprising amuco-adhesive material or polymer and further coated with an outer layercomprising an enteric material or polymer. In certain embodiments, thedrug-containing core of the controlled release component will comprisesa rate controlling material, which may be mixed with the drug to form acontrolled release matrix core, coated onto the drug containing core toform an undercoat below the coating or layer comprising themuco-adhesive material, incorporated into the coating or layercomprising the muco-adhesive material or polymer, or a combinationthereof. In some embodiments, the controlled release material andmuco-adhesive material may be mixed together with the LD and/or an esterof LD or salts thereof to form a controlled release/muco-adhesive core.

The immediate release component may be formulated as a powder, coating,tablet, mini-tablet, bead, pellet, granule or combination thereof thatis separate from or part of the controlled release component. In certainembodiments, the immediate release component is in the form of a powder,tablet, mini-tablet, pellet, bead or granule that is separate from thecontrolled release component. In alternative embodiments the immediaterelease component may also be applied as an immediate release coating orlayer onto one or more of the controlled release components. In certainembodiments, the immediate release component may be applied to orsurround the enteric coating of the controlled release component.

In another embodiment of the invention, the oral dosage forms comprise(1) one or more controlled release components comprising a LD and/or anester of LD or salts thereof and (2) one or more immediate releasecomponents comprising LD and/or an ester of LD or salts thereof and (3)a decarboxylase inhibitor component, preferably a CD component. Thedecarboxylase inhibitor component may be formulated as a powder,coating, tablet, mini-tablet, bead, pellet, granule or combinationthereof. The decarboxylase component may be in an immediate releaseform, a controlled release form or immediate release and controlledrelease forms. The decarboxylase inhibitor may be co-formulated with (1)one or more of the controlled release components comprising a LD and/oran ester of LD or salts thereof and/or (2) with one or more of theimmediate release components comprising LD and/or an ester of LD orsalts thereof. Alternatively the decarboxylase inhibitor may beformulated separately from the one or more controlled release componentscomprising a LD and/or an ester of LD or salts thereof and/or the one ormore immediate release components comprising LD and/or an ester of LD orsalts thereof.

The controlled release component may comprise drug-containing corescontaining both LD and/or an ester of LD or a salt thereof and adecarboxylase inhibitor such as CD, or the LD and/or ester of LD or saltthereof may be in separate controlled release components from thatcontaining the decarboxylase inhibitor. In one embodiment of theinvention, the controlled release component comprises an LD-containingcore free or substantially free of a decarboxylase inhibitor such as CD.In this embodiment, substantially free means 15% or less of the totalamount of decarboxylase inhibitor in the dosage form is in thecontrolled release component(s), preferably 10% or less, 9% or less, 8%or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2%or less, or 1% or less. The immediate release component of thisembodiment may comprise a combination of LD and/or an ester of LD or asalt thereof and a decarboxylase inhibitor. The LD and/or ester of LD orsalt thereof may also be in a separate immediate release component fromthe decarboxylase inhibitor.

In a preferred embodiment of the invention, the oral dosage formscomprise (1) one or more controlled release components comprising LDand/or ester of LD or salt thereof and (2) one or more immediate releasecomponents comprising LD and/or ester of LD or salt thereof and CD. Inthis embodiment, the controlled release component may comprise adrug-containing core coated with a first layer comprising a ratecontrolling material or polymer, a second layer comprising amuco-adhesive material or polymer and an outer or third layer comprisingan enteric material or polymer (see, e.g., FIG. 1 ). Additional coatingsor layers such as cosmetic coatings or non-functional coatings such aswater soluble seal coatings can also be added to separate the core,first, second and/or third layers or to overcoat the third layer. Thesecosmetic or non-functional coatings may also be used to separate animmediate release component from the controlled release component aswell as to apply or adhere an immediate release component to thecontrolled release component. As used herein a non-functional orcosmetic coating should dissolve within 30 minutes, 25 minutes, 20minutes, 15 minutes, 10 minutes or 5 minutes when the composition withthe non-functional or cosmetic coating as the outer most coating isplaced in a USP dissolution apparatus, either a Type I or II with500-900 ml of an aqueous media with a pH of 1-7.

In accordance with the practice of the invention, the components of theinvention may be obtained by any methods commonly used in the art suchas blending, mixing, granulation and/or coating processes, including,but not limited to, wet-granulation, fluid bed granulation/coating, orextrusion/spheronization, as are well-known in the pharmaceutical arts.The compositions may also be formed with other conventional formulationtechniques such as compression and/or slugging. In addition to drugssuch as LD and CD, the controlled release components and/or theimmediate release components may further contain conventionalpharmaceutically acceptable excipients such as lubricants, fillers,binders, disintegrants, glidants, surfactants (sometimes referred to aswetting agents), pH adjusting agents, antioxidants or mixtures of theforegoing.

In an embodiment of the invention, the controlled release and/orimmediate release components are multiparticulates that areencapsulated, preferably in a hard gelatin capsule. Themultiparticulates may be in a form that can be sprinkled directly ontofood or liquids for easy ingestion.

The active agents, such as CD, LD and/or LD esters and salts thereof,may be combined and dispersed throughout the drug-containing core. Inanother embodiment, the active agents may be present in the center ofthe drug-containing core or layered/coated on an inert core such as asugar sphere, microcrystalline cellulose sphere, glass sphere, plasticsphere or combination thereof.

In an embodiment of the invention, the oral dosage forms may comprisetwo or more controlled release components that release the drug(s) suchas CD, LD, an ester of LD or salts thereof at different rates. In thisembodiment, the oral dosage forms contain at least two controlledrelease components differing in type, number, thickness and/orcomposition of first coating comprising the rate controlling material,the second coating comprising the muco-adhesive material and/or thethird coating comprising the enteric material.

Examples of LD include but are not limited to levodopa, L-DOPA,L-3,4-dihydroxyphenylalanine, and(S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid.

An example of a decarboxylase inhibitor includes, but is not limited toCD. Additional decarboxylase inhibitors include alpha methyldopa,benserazide (Ro4-4602), and alpha-difluoromethyl-DOPA (DFMD) or saltsthereof. In a preferred embodiment, the decarboxylase inhibitor iscarbidopa.

An example of an ester of LD is a levodopa ethyl ester (LDEE; ethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; CAS Number: 37178-37-3)and having the structure:

(levodopa ethyl ester; CAS Number 37178-37-3).

Additional examples of esters of LD include, but are not limited to:

levodopa butyl ester (butyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; CAS Number: 39638-52-3)having the structure:

levodopa propyl ester; levodopa propyl ester (propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; CAS Number: 39638-51-2)having the structure:

and levodopa methyl ester (methyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; CAS Number: 7101-51-1),having the structure:

The ester of LD may be a salt, including, for example, a hydrated salt.The salt of LD esters may comprise an organic or inorganic acid additionsalt such as an octonoate salt, myristate salt, succinate salt,succinate dihydrate salt, fumarate salt, fumarate dihydrate salt,mesylate salt, tartrate salt, sulfate salt, alkyl sulfate salt, maleatesalt, citrate salt, phosphate salt, acetate salt, lactate salt, nitratesalt, hydrochloride salt, hydrobromide salt, hydroidioide salt orcombination thereof.

For example, the succinate salt of an ester of LD or the succinatedihydrate salt may be a levodopa ethyl ester succinate (LDEE-S) orlevodopa ethyl ester succinate dihydrate (LDEE-S-dihydrate orLDEE-S(d)).

As used herein, “levodopa equivalence” or “LD equivalence” means thatamount of levodopa ester or salts thereof that contain equivalentamounts of levodopa, based on weight equivalence. For example, based onthe molecular weights, 306 mg of levodopa ethyl estersuccinate-dihydrate (LDEE-S-dihydrate) is equivalent to 228 mg oflevodopa ethyl ester (LDEE) and to 200 mg levodopa (LD).

The muco-adhesive material employed in the present invention may be ahomogenous muco-adhesive material, i.e., a single type of muco-adhesivematerial or polymer, or may comprise multiple types of muco-adhesivematerials and/or polymers. The muco-adhesive material or polymer maypossess certain characteristics such as being hydrophilic, hydrophobic,cationic, anionic and/or biocompatible and include multiple hydrogenbonding groups, hydrophobic surfaces, positively charged groups and/ornegatively charged groups for adhesion to a mucosal surface so that thecontrolled release component can be held, prolonged or slowed at thesite of absorption, thereby allowing the release of the LD or ester ofLD from the controlled release component at the desired absorption siteand thereby increase bioavailability. Further, the muco-adhesivematerial or polymer may be natural, synthetic or from a biologicalsource. Further still, the muco-adhesive material or polymer may becomposed of a single polymer or a combination of two or more differentpolymers. In one embodiment, the polymers may range in size from 10,000daltons to 1,000,000 daltons and more preferably 20,000 daltons to200,000 daltons.

An example of a muco-adhesive polymer includes, but is not limited to, abasic methacrylate copolymer, such as an amino methacrylate copolymer. Apreferred example of a methacrylate copolymer is a basic butylatedmethacrylate copolymer, an amino methacrylate copolymer, or aminoalkylmethacrylate copolymer, such as Eudragit® El00 (poly(butylmethacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methylmethacrylate) 1:2:1; CAS number: 24938-16-7; Evonik Industries).EUDRAGIT® E100 is a cationic copolymer based on dimethylaminoethylmethacrylate, butyl methacrylate, and methyl methacrylate with a ratioof 2:1:1 with the following monomer

wherein Y is nitrogen. In a preferred embodiment, the average molarweight of EUDRAGIT® El00 is approximately 150,000 g/mol.

Other examples of muco-adhesive materials or polymers include, but arenot limited to, a glyceride, steroidal detergent, polycarbophil (CASNumber 9003-97-8; Noveon® AA-1; Lubrizol Corp.), carbomer, cellulosics,chitosan

(CAS Number: 9012-76-4; Chitopharm® S with molecular weight range of50,000 to 1,000,000 daltons), diethylaminodextran,diethylaminoethyldextran, polygalactosamine, polylysine, polyornithine,prolamin, polyimine, hyaluronic acid, sodium alginate,hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC),sodium carboxymethylcellulose (sodium CMC) and alginate (CAS Number:9005-32-7) or combination thereof. Alginate is a homopolymer orheteropolymer composed of P-D-mannuronate (M) monomers, a-L-guluronate(G) monomers, or mixture of P-D-mannuronate and a-L-guluronate monomers

linked through (1→4) or (1,4)-glycosidic bonds. The (1,4)-glycosidiclinkages present in alginates are: β-D-mannuronate-(1,4)-β-D-mannuronate(MM), β-D-mannuronate-(1,4)-α-L-guluronate (MG),α-L-guluronate-(1,4)-β-D-mannuronate (GM) andα-L-guluronate-(1,4)-α-L-guluronate (GG), as can be seen below:

An alginate may be in the form of a polyanion or in the form of an acid,such as alginic acid. Further, alginate may be in the form of a salt ofalginic acid, such as sodium alginate, potassium alginate, ammoniumalginate, triethanolamine alginate, magnesium alginate or calciumalginate. Alternatively, alginate may be in the form of an ester ofalginic acid such as propylene glycol alginate.

The muco-adhesive material or polymer may constitute about 1-75% of themass of the controlled release component, preferably about 2-70% of themass of the controlled release component, most preferably about 3-50% ofthe mass of the controlled release component. Preferably, themuco-adhesive material or polymer is Eudragit® E 100 alone or combinedwith at least one additional muco-adhesive material. The muco-adhesivematerial or polymer percentages of mass stated above are based on amultiparticulate with a bead size between 0.8 to 1.2 mm. If the beadsize is larger or smaller than 0.8 to 1.2 mm, the skilled artisan willunderstand that the mass percentage described above should be adjustedaccordingly.

Alternatively, the muco-adhesive material or polymer is a materialcapable of forming a positive ionic charge at the pHs present in thehuman gastro-intestinal tract. It is believed that the positive chargemay allow the muco-adhesive material to interact with the negativecharge of the intestinal walls and thereby slow or delay thegastrointestinal transit time of the controlled release component.

Enteric coating materials or polymers are known in the art. In general,enteric coating polymers are designed to prevent drug release from anoral solid dosage form in the low pH environment of the stomach, therebydelaying drug release until the dosage form reaches the small intestine.As such, the controlled release components of the invention have an invitro release profile with minimal release of the active agent at pH1.0. In the controlled release formulations of the invention, it isbelieved the third or outer enteric coating layer provides an additionaladvantage in preventing agglomeration of the controlled releasecomponents. That is, the enteric coat layer prevents the controlledrelease muco-adhesive components from sticking together in the low pHenvironment of the stomach.

The preferred enteric materials are shellac (esters of aleurtic acid),zein, cellulose acetate phthalate (CAP), poly(methacrylic acid-co-methylmethacrylate), poly(methacrylic acid-co-ethyl methacrylate), celluloseacetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP),hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropylmethylcellulose acetate succinates. The preferred enteric polymersrelease at a pH of greater than or equal to pH 5.5. Examples includeEudragit® L100 or Eudragit® L100-55. The enteric polymers may constituteabout 1-40% of the mass of the controlled release component, preferablyabout 1.5-30%, most preferably about 1.5-25%. The enteric-coated polymerpercentages stated above are based on a multiparticulate bead sizebetween 0.8-1.2 mm. If the bead size is smaller or larger, the skilledartisan will understand that the mass percentage described above shouldbe adjusted accordingly.

The third or outer enteric coating should be designed to dissolve at apH greater than 5.0, at a pH of 5.5 or higher, at a pH of 6.0 or higheror a pH of 6.5 or higher. In certain embodiments, the third or outerenteric coating should be designed to dissolve at a pH in the range of5.0 to 6.4, preferably in the range of 5.0 to 6.0.

The enteric coating polymer may comprise a methacrylic acid copolymer ormultiple types of methacrylic acid copolymers. The methacrylic copolymermay comprise any of Eudragit® L 30 D-55

(poly(methacrylic acid-co-ethyl acrylate) 1:1; CAS Number 25212-88-8;Evonik Industries), Eudragit® L 100-55

(poly(methacrylic acid-co-ethyl acrylate) 1:1; CAS Number 25212-88-8;Evonik Industries), Eudragit® L 100

(poly(methacrylic acid-co-methyl methacrylate) 1:1; CAS Number25086-15-1; Evonik 15 Industries), Eudragit® L 12,5

(poly(methacrylic acid-co-methyl methacrylate) 1:1; CAS Number25086-15-1; Evonik Industries); Eudragit® S 100

(poly(methacrylic acid-co-methyl methacrylate) 1:2; CAS Number25086-15-1; Evonik Industries), Eudragit® S 12,5

(poly(methacrylic acid-co-methyl methacrylate) 1:2; CAS Number25086-15-1; Evonik Industries), and Eudragit® FS 30 D

(poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1;CAS Number 26936-24-3; Evonik Industries) or a combination thereof.

In a preferred embodiment of present invention, the controlled releasecomponent comprises a first rate controlling coating over thedrug-containing core (i.e. applied to or surrounding the drug containingcore with or without a seal coating), a second coating comprising amuco-adhesive material that is applied to or surrounding the ratecontrolling coating (with or without a seal coating) and a third coatingcomprising an enteric material that is applied to or surrounding thesecond coating (with or without a seal coating). The first ratecontrolling coating may comprise a controlled release material orpolymer such as ethylcellulose, cellulose acetate, Eudragit® E,Eudragit® RS, Eudragit® RL, and Eudragit® NE, or mixtures thereof.Preferably, the controlled release materials are not soluble in water atneutral pH. Additional the controlled release materials or polymers thatmay be used are described in U.S. Pat. No. 5,002,776 which isincorporated herein by reference. In certain embodiments the controlledrelease material or polymer is cellulose acetate, ethylcellulose or amixture thereof. The first or rate controlling coating may furthercomprise a pore forming agent or a flux enhancer to adjust the releaserate of the drug from the core. Preferably, the pore forming agent orflux enhancer is a water soluble material such as a salt, i.e., NaCl,KCl, a sugar, i.e., lactose, sucrose, mannitol, povidone, copovidone,polyethylene glycol, hydroxypropyl cellulose, hydroxypropylmethylcelluose or combinations thereof. If the pore forming agent orflux enhancer is a water soluble polymer, it should have a low molecularweight such as below 100,000, preferably below 50,000 and/or shouldrapidly dissolve in water, i.e., 2 wt % of the water soluble polymershould dissolve in 100 ml of water within 15 minutes or less, preferably10 minutes or less, and most preferably 5 minutes or less at 25° C.

The controlled release component may also comprise a hydrophobiccontrolled release material in addition to or in place of the controlledrelease materials described above. Examples of hydrophobic materialsthat can be used include beeswax, white wax, emulsifying wax,hydrogenated vegetable oil, hydrogenated castor oil, microcrystallinewax, cetyl alcohol, stearyl alcohol, free wax acids such as stearicacid, esters of wax acids, propylene glycol monostearate, glycerolmonostearate, carnauba wax, palm wax, candelilla wax, lignite wax,ozokerite, ceresin wax, lardaceine, China wax and mixtures thereof.Other possible controlled release excipients useful in the presentinvention include saturated hydrocarbons having from 25 to 31 carbonatoms, saturated alcohols having from 25 to 31 carbon atoms, saturatedmonocarboxylic acids having from 25 to 31 carbon atoms, esters obtainedfrom said alcohols, and monocarboxylic acids which are described in U.S.Pat. No. 6,923,984, incorporated herein by reference.

In an alternate embodiment, the controlled release component comprises amatrix core comprising a mixture of a controlled release material, whichmay be the afore-described controlled release materials and/orhydrophobic materials and the drug, i.e., CD, LD and/or ester of LD orsalts thereof and/or decarboxylase inhibitor. The matrix core mayfurther comprise one or more pharmaceutically acceptable excipients suchas lubricants, fillers, binders, disintegrants, glidants, surfactants(sometimes referred to as wetting agents), pH adjusting agents,antioxidants or mixtures of the foregoing. In this embodiment, thematrix core may be further coated with a rate controlling coating orpolymer before being coated with the muco-adhesive coating and the outerenteric coating.

In another alternate embodiment, the controlled release component mayincorporate a controlled release material, which may be theafore-described controlled release materials and/or hydrophobicmaterial, into the muco-adhesive coating. The muco-adhesive material mayalso function as the controlled release material or contribute to thecontrolled release of the drug form the controlled release component.

The controlled release material may constitute about 1-35% of the massof the controlled release component, preferably about 2-30% and mostpreferably about 3-25%.

The muco-adhesive coating or layer and enteric coating or layer employedin the present invention may further comprise one or morepharmaceutically acceptable excipients such as plasticizers, lubricants,fillers, binders, disintegrants, glidants, surfactants (sometimesreferred to as wetting agents), pH adjusting agents, antioxidants, ormixtures of the foregoing in addition to the muco-adhesive material andenteric material.

Some commonly known plasticizers include adipate, azelate, enzoate,citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-butylcitrate, acetyl tri-n-butyl citrate, citric acid esters, and thosedescribed in the Encyclopedia of Polymer Science and Technology, Vol. 10(1969), published by John Wiley & Sons. The preferred plasticizers aretriacetin, acetylated monoglyceride, grape seed oil, olive oil, sesameoil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol,diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate,diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate,tributylcitrate, glyceroltributyrate and combinations thereof. Dependingon the particular plasticizer, amounts from about 0% to about 25%, andpreferably about 2% to about 15%, of the plasticizer can be used basedupon the total weight of the controlled release, muco-adhesive and/orenteric coating.

Lubricants useful in pharmaceutical formulations are known in the art.Examples of a suitable lubricant include, but are not limited to,stearic acid, lauric acid, myristic acid, palmitic acid, fatty acid,magnesium stearate, calcium stearate, zinc stearate, sodium stearate,Stear-O-Wet®, sodium stearyl fumarate, salt of a fatty acid, metallicsalt of fatty acid, glyceryl monostearate, glyceryl tribehenate,glyceryl dibehenate, Compritol® 888 ATO, glyceride ester, sorbitanmonostearate, sucrose monopalmitate, sugar ester, fatty acid ester,talc, hydrated magnesium silicate, PEG 4000, boric acid, Carbowax (PEG)4000/6000, sodium oleate, sodium benzoate, sodium acetate, sodium laurylsulfate, magnesium lauryl sulfate, Sterotex, wax, or mixture thereof.

Examples of fillers that may be employed in the composition of thepresent invention include sugars, such as lactose, sucrose, mannitiol,dibasic calcium phosphate, microcrystalline cellulose, calciumcarbonate, magnesium carbonate, calcium sulfate, powdered cellulose,silicified microcrystalline cellulose, magnesium carbonate, magnesiumoxide, starch, and mixtures thereof. The filler may constitute about1-50% of the mass of the controlled release component, preferably about2-45% and most preferably about 5-40%. Similarly, the filler mayconstitute about 1-50% of the mass of the immediate release component,preferably about 2-45% and most preferably about 5-40%.

Examples of binders that may be employed in the compositions of thepresent invention include acacia, povidone, hypromellose, hydroxypropylcellulose, hydroxyethyl cellulose, polyethylene oxide,polymethacrylates, methyl cellulose, ethyl cellulose, pregelatinizedstarch, gelatin, tragacanth, zein, or mixtures thereof. Preferably, thebinder is selected from povidone, hypromellose, hydroxypropyl cellulose,hydroxyethyl cellulose, polymethacrylates, methyl cellulose, gelatin andethyl cellulose, or mixtures thereof. Especially preferred bindersinclude water soluble binders such as povidone, hypromellose,hydroxypropyl cellulose, gelatin and mixtures thereof. The binder mayconstitute about 0.1-15% of the mass of the controlled releasecomponent, preferably about 0.2-10% and most preferably about 0.5-5%.The binder may constitute about 0.1-15% of the mass of the immediaterelease component, preferably about 0.2-10% and most preferably about0.5-5%.

Examples of disintegrants that may be employed in the compositions ofthe present invention include croscarmellose sodium, starch,crospovidone, sodium starch glycolate, alginic acid, calciumcarboxymethylcellulose, sodium carboxymethylcellulose, calciumcarboxymethylcellulose, powdered cellulose, chitosan, guar gum,magnesium aluminium silicate, methylcellulose, sodium alginate, andmixtures thereof. The disintegrant may constitute about 0.1-15% of themass of the immediate release component, preferably about 0.2-10% andmost preferably about 0.5-5%.

Examples of glidants that may be employed in the compositions of thepresent invention include colloidal silicon dioxide, cornstarch, talc ormixtures thereof.

One or more surfactants may also be employed in the compositions of thepresent invention. The surfactant may be a non-ionic surfactant or anionic surfactant. Examples of non-ionic surfactants includepolyethoxylated castor oil, a polyoxyethylene alkyl ester, apolyglycolyzed glyceride, a sorbitan fatty acid ester, a glycerin fattyacid ester, a fatty acid polyglyceride, a fatty acid alcohol polyglycolether, acetylene glycol, acetylene alcohol, an oxyalkylene blockpolymer, a polyoxyethylene alkyl ether, a polyoxyethylene alkylarylether, a polyoxyethylene styrylaryl ether, a polyoxyethylene glycolalkyl ether, a polyoxyethylene fatty acid ester, a polyoxyethylenesorbitan fatty acid ester, a polyoxyethylene glycerin fatty acid ester,a polyoxyethylene hydrogenated castor oil, a polyoxypropylene fatty acidester, or a mixture of the foregoing. A further listing of possiblenon-ionic surfactants can be found on pages 1243-1249 of Martindale, TheExtra Pharmacopoeia 29^(th) ed. which is incorporated herein byreference.

In certain embodiments, the non-ionic surfactants may comprise fattyalcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitanester ethoxylates alkyl polyglycosides, mixtures thereof, and the like.Certain non-ionic surfactants include polyoxyethylene derivatives ofpolyol esters, such as Polysorbate 20 (TWEEN 20®), Polysorbate 40 (TWEEN40®) Polysorbate 60 (TWEEN 60®), and Polysorbate 80 (TWEEN 80®).

In certain embodiments, the non-ionic surfactant may also comprised-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS),nonoxinols, poloxamers, sorbitan monolaurate, sorbitan monooleate,sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate,sorbitan trioleate, tyloxapol, and mixtures of the foregoing.

Any variety of ionic surfactants may also be incorporated into thecompositions of the present invention. Suitable ionic surfactantsinclude, but are not limited to, carboxylates such as soaps, acyllactylates, acyl amides of amino acids, esters of sulfuric acid such asalkyl sulfates and ethoxylated alkyl sulfates, sulfonates such as alkylbenzene sulfonates, acyl isethionates, acyl taurates andsulfosuccinates, phosphates, quaternary ammonium salts, and ethoxylatedamines. An example of a preferred ionic surfactant is sodium laurylsulfate.

The surfactant may constitute about 0.1-15% of the mass of thecontrolled release component or the immediate release component,preferably about 0.2-10% and most preferably about 0.5-5%.

Examples of pH adjusting agents that may be employed in the compositionsof the present invention include pharmaceutically acceptable acids orbases which may be present to adjust the pH of intermediate compositionsleading up to the final compositions and to adjust the pH of the drugenvironment of final compositions to a desired or optimum pH range.Representative examples of pharmaceutically acceptable acids that may beused include, but are not limited to, acetic acid, citric acid, fumaricacid, hydrochloric acid, malic acid, nitric acid, phosphoric acid,propionic acid, sulfuric acid, tartaric acid, and mixtures thereof.Representative examples of pharmaceutically acceptable bases that may beused include but are not limited to ammonia, ammonium carbonate,diethanolamine, potassium hydroxide, sodium bicarbonate, sodiumcarbonate, sodium hydroxide, trolamine, and mixtures thereof. In certainembodiments the pH adjusting agent is an acid, preferably an organicacid and will constitute about 0.5-20% of the mass of the controlledrelease component, preferably about 0.75-15% and most preferably about1-10%. Alternatively, the pH adjusting agent is an acid, preferably anorganic acid and will be present in the controlled release component ina molar ratio of acid to levodopa of about 1:4 to about 4:1, preferablyabout 1:3 to about 3:1 and most preferably about 1:2 to about 2:1.Certain embodiments of the present invention, the immediate releasecomponents, the controlled release components and/or the final oraldosage forms are free or substantially free of a pH adjusting acid,preferably a pH adjusting organic acid and most preferably a pHadjusting carboxylic acid such as acetic acid, citric acid, fumaricacid, malic acid, propionic acid, tartaric acid, and mixtures thereof

Examples of antioxidants that may be employed in the compositions of thepresent invention include ascorbic acid, ascorbyl palmitate, butylatedhydroxyanisole, butylated hydroxytoluene, hypophosphorous acid,monothioglycerol, potassium metabisulfate, propyl gallate, sodiumbisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfate, sodiumsulfate, sodium thiosulfate, sodium dioxide, tocopherol, and mixturesthereof.

In an embodiment of the invention, the CD and the LD or LD equivalenceare present in the dosage form of the invention in a weight ratio ofabout 1:1 to about 1:10, preferably about 1:3 to about 1:5 and mostpreferably about 1:4. Certain embodiments comprise CD and LD in a ratioof about 1:4 and wherein all or substantially all of the CD is in theimmediate release component.

Examples of useful amounts of LD or LD equivalence to CD include: (a)200 mg:31.25 mg; (b) 200 mg:50 mg; (c) 255.6 mg:50 mg; (d) 360 mg:50 mg;(e) 95 mg:23.75 mg; (f) 145 mg:36.25 mg; (g) 195 mg:48.75 mg; (h) 245mg:61.25 mg; or (i) 390 mg:97.5 mg; with each value capable of varyingby ±10%. Further examples include amounts of LD:CD or LD equivalence:CDas follows: (a) 95 mg:23.75 mg; (b) 145 mg:36.25 mg; (c) 195 mg:48.75mg; or (d) 245 mg:61.25 mg; with each value capable of varying by ±10%.Additional examples of the present invention include dosage forms,comprising: (a) about 140 mg LD and about 35 mg of CD; (b) about 210 mgLD and about 52.5 mg of CD; (c) about 280 mg LD and about 70 mg of CD;and (d) about 350 mg LD and about 87.5 mg of CD. The foregoing valuesare based on the weight of anhydrous CD. If a monohydrate form of CD isemployed the amounts will be slightly higher. For example 35 mg ofanhydrous CD is equivalent to 37.79 mg of CD monohydrate; similarly 70mg of anhydrous CD is equivalent to 75.58 mg of CD monohydrate.

In an embodiment of the invention, the immediate release component maycomprise less LD or LD equivalence than the controlled releasecomponent. For example, the ratio of LD or LD equivalence in theimmediate release component to that in the controlled release componentcan be in the range of 0.15 to 0.49. For example, a ratio in weight ofLD or LD equivalence in the controlled release component:immediaterelease component is at least about 2:1, most preferably 3:1. Preferablythe amount of LD or LD equivalence in the immediate release componentshould provide a therapeutic dose of LD within one hour or less afteradministration of the dosage form, preferably within 45 minutes or lessafter administration and most preferably about 30 minutes or less afteradministration.

As discussed above, in certain embodiments comprising a decarboxylaseinhibitor such as CD, all or substantially all of decarboxylaseinhibitor should be in the immediate release component. The amount ofimmediate release decarboxylase inhibitor, preferably CD, in theimmediate release component(s) should range from about 75% to about 100%based on the total amount of decarboxylase inhibitor in the oral dosageforms, preferably about 80% to 100%, and most preferably about 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99 or 100%.

In one embodiment of the invention, the controlled release componentcomprise one or more, beads, pellets, tablets, mini-tablets or granuleshaving a size that passes through 12, 14, or 16 mesh but may be retainedon 18, 24 or 25 mesh screens. Further, the beads, pellets, tablets,mini-tablets or granules may have a size that passes through 14 mesh butmay be retained on 18 or 24 mesh screens. In certain embodiments, thedosage forms of the invention comprise a plurality beads, pellets,tablets, mini-tablets or granules having a size that passes through 12,14, or 16 mesh but may be retained on 18, 24 or 25 mesh screens.

The controlled release component will have an in vitro dissolutionprofile showing minimal release of the LD and/or ester of the LD or asalt thereof at pH 1.0 and extended release of the LD and/or ester of LDor a salt thereof near neutral pH, for example at or near pH 7. Forexample, minimal release may entail less than 20% release of LD,preferably less than 10%, most preferably less than 5% using UnitedStates Pharmacopeia (USP) I dissolution method at agitation speed of 75rpm in Simulated Gastric Fluid (pH 1.0, without enzyme) for 2 hrs.Further, extended release may involve release at over at least four andup to an additional 8 hours at or near pH 7, upon changing to SimulatedIntestinal Fluid (pH 7.0, without enzyme) after first 2 hrs in SimulatedGastric Fluid (pH 1.0, without enzyme) using USP I dissolution method atagitation speed of 75 rpm. Further still, as used here, at or near pH 7includes a pH at or about pH 6.5, 6.6, 6.7, 6.8 6.9, 7.1, 7.2, 7.3, 7.4,7.5 or 7.6.

The oral dosage forms of the present invention should comprise one ormore immediate release components and one or more controlled releasecomponents wherein following administration to a human patient theimmediate release component(s) should provide a therapeutic dose of LDwithin one hour or less after administration of the dosage form,preferably within 45 minutes or less after administration and mostpreferably about 30 minutes or less after administration. After thetherapeutic plasma level of LD is obtained by the immediate releasecomponent(s), the controlled release component(s) should provide and/ormaintain a therapeutic plasma level of LD over a period of at least 4-12hours, preferably 6-12 hours and most preferably 5, 6, 7, 8, 9, 10, 11or 12 hours after administration. To obtain this therapeutic level, thecontrolled release component(s) should exhibit the following in vitrorelease profiles when tested using a USP Type I or II apparatus, at 37°C., with a rotational speed of 75 rpms and 900 ml of an aqueous mediawith a pH between 6.8-7.4 and preferably at a pH of 7:

Levodopa Released Time Preferred More Preferred Most Preferred 2  0-60%10-55% 15-50% 4 25-90% 30-85% 35-80% 6 35-100% 40-100% 50-100%

The amount of LD released in the above table is based on the totalamount of LD or ester of LD or salt thereof present in the controlledrelease component(s). In certain embodiments the controlled releasecomponent(s) should also release less than 25% of the LD or ester of LDor salt thereof, preferably less than 20% and most preferably less than15% when tested using a USP Type I or II apparatus, at 37° C., with arotational speed of 75 rpms and 900 ml of an aqueous media with a pH of1 for 2 hours.

In certain embodiments the oral dosage forms of the present inventioncomprises: (i) one or more immediate release components comprising LDand CD and (ii) one or more controlled release components, i.e.,controlled release particles such as beads, pellets, tablets,mini-tablets, or granules comprising: (a) a core comprising LD,optionally CD and at least one pharmaceutically acceptable excipient,(b) a layer or coating surrounding the core comprising a muco-adhesivematerial and (c) an outer coating comprising an enteric materialsurrounding the muco-adhesive coating (b). This embodiment may alsocomprise a controlled release material in the core or a coatingcomprising a controlled release material surrounding the core andbeneath the coating comprising the muco-adhesive material as well ascosmetic and/or non-functional seal coatings as previously described.When this embodiment of the dosage form of the present invention istested using a USP Type I or Type II apparatus with 500-900 mL of anaqueous medium with a pH from about 1 to about 7.5, about 75% to 100% ofthe CD is released within 30 minutes, preferably about 85% to 100% ofthe CD is released within 30 minutes and most preferably about 90% to100% of the CD is released within 30 minutes. In addition, when thisembodiment of the dosage form is tested using a USP Type I or Type IIapparatus and 500-900 mL of an aqueous medium with a pH from about 1 toabout 4.0, about 15% to 45% of the LD is released within 30 minutes,preferably about 20% to 40% of the LD is released within 30 minutes andmost preferably about 25% to 35% of the LD is released within 30minutes. When this embodiment of the dosage form is tested using a USPType I apparatus, at 37° C.±0.5° C., with a rotational speed of 75 rpmsand 500-900 ml of simulated gastric fluid for 2 hours and pH 6.8phosphate buffer thereafter the following LD in vitro profile isexhibited:

Levodopa Released Time (hour) Preferred More Preferred Most Preferred 220-60% 25-55% 30-50% 3 40-80% 45-75% 50-75% 4 60-100% 65-100% 70-100% 7hours NLT 80% NLT 85% NLT 90% NLT = Not Less Than.

In a further embodiment, the present invention comprises: a) one or moreimmediate release components as previously described; b) one or morecontrolled release components as previously described and c) one or moreenteric coated components. The enteric coated component comprises a corecomprising LD or ester of LD or salt thereof and/or a decarboxylaseinhibitor and at least one pharmaceutically acceptable excipient aspreviously described and an enteric coating. The enteric coatedcomponent will release 100% of the LD or ester of LD or salt thereofand/or a decarboxylase inhibitor within 90 minutes, preferably 60minutes and most preferably within 45 minutes when tested using a USPType I or II apparatus, at 37° C., with a rotational speed of 75 rpmsand 900 ml of an aqueous media with a pH between 6.8-7.4, preferably atpH 7. The enteric coated component will also release less than 25% ofthe LD or ester of LD or salt, preferably less than 20% and mostpreferably less than 15% when tested using a USP Type I or II apparatus,at 37° C., with a rotational speed of 75 rpms and 900 ml of an aqueousmedia with a pH of 1.

The LD and/or ester of LD or a salt thereof released from the controlledrelease component(s) may produce an in vivo LD a plasma profile (e.g.,mean in vivo LD plasma profile) comprising a peak occurring not beforeabout two hours after administration to a subject and provides at leastthree hour duration for LD plasma concentration above 50% the maximumvalue of the peak concentration (C_(max)). In another embodiment, in theplasma profile, the peak occurs after about one and a half hours afteradministration to the subject and exhibits at least a four-hour durationfor LD plasma concentration at or above 50% of C_(max). By way ofexample, the profile may be achieved under fasting conditions.

When the formulation of the invention comprises an immediate releasecomponent and a controlled release component, the in vivo LD plasmaprofile following oral administration of the dosage form of the presentinvention to a subject may comprise a time of administration of an oraldosage form; an LD plasma concentration corresponding to C_(max)occurring within about 6 hours or 7 hours after administration of thedosage form; a mean time to reach 50% of C_(max) within one hour ofadministration, more preferably within 30 minutes. The time to 50% ofC_(max) is less than one hour and 50% of C_(max) is maintained for atleast 5.0 hours. The time after administration of the dosage form whenthe maximum plasma concentration is reached (T_(max)) is between 30minutes and 7 hours. Preferably, the LD plasma level is maintained at orabove 50% of C_(max) for at least 5.5 hours, more preferably, for atleast 6.0 hours, even more preferably, for at least 6.5 hours, and mostpreferably for at least 7.0 hours.

It is understood by those skilled in the art that the pharmacokineticparameters recited herein may be obtained by single or multidose dosestudies to healthy subjects or PD patients unless specifically stated.It is also understood that the pharmacokinetic parameters recited hereinmay be obtained under fed or fasting conditions. It is furtherunderstood that the pharmacokinetic parameters recited herein are meanvalues, unless specifically stated, obtained from single or multidosestudies employing at least 3 or more subjects or patients.

In one embodiment, the dosage forms of the invention may have a ratio ofsaid C_(max) to the mass of LD or LD equivalence. The concentration maybe measured in units of ng/mL, to the mass of LD or LD equivalence inthe formulation, where said mass is measured in mg, of between 2:1 and6:1. The ratio may be between 2.5:1 and 5.5:1, preferably, greater thanor equal to about 3:1.

The combination of immediate release components and controlled releasecomponents of the invention provide the near infusion-like profile asevident from the plateau in the LD plasma profile (see, e.g., FIG. 5 ).The LD C_(max) itself is not clinically relevant. What is clinicallyrelevant is the time to reach a therapeutic level of LD (e.g., an LDlevel of 50% C_(max)) and the time maintained at or above thetherapeutic level (e.g., 50% C_(max)). The short time to reach atherapeutic LD level is associated with a faster “on” time for PDpatients, whereas the prolonged period at or above therapeutic levelsprovides the desired steady “infusion-like” profile.

It is an advantage of the present invention to provide a sustained LDplasma concentration for a duration greater than 5 hrs and a moreconsistent duration with percent coefficient of variation (CV) of meanduration of LD plasma concentrations >50% C_(max) of less than 35%,preferably less than 30%.

The skilled artisan will appreciate that daily dosages having an amountof active agent sufficient or effective to treat diseases associatedwith reduced or impaired dopamine levels may generally contain fromabout 25 mg to about 6000 mg of LD or LD equivalence dose in combinationwith from about 5 mg to about 1500 mg of CD.

Dosage forms of the present invention may contain 25-750 mg of LD or LDequivalence, preferably about 50-500 mg and most preferably about 80-400mg wherein 25% to 50% of the total LD or LD equivalence is in theimmediate release component, preferably 25% to 40% and most preferably25% to 35%. Further, dosage forms of the present invention may containCD ranging from 25-300 mg, preferably 25-200 mg and most preferably30-150 mg wherein all or substantially all of the CD is in the immediaterelease component.

By way of example, the total daily dose of LD from the dosage forms ofthe invention may be less than about 2500 mg. For example, the totaldaily LD dose may be between 800 mg to 2500 mg. In a further example,the total daily LD dose may be about 855 mg, 1140 mg, 1170 mg, 1305 mg,1755 mg, 2205 mg, or 2340 mg. In another embodiment, the total daily CDdose may be about 100 mg to 800 mg. The total daily dose will dependupon the patient's individual characteristics such as age, sex, weightand severity of PD symptoms.

The dosing frequency may also vary, depending on the need of thesubject. For example, the dosing frequency of the formulations of theinvention may be two, three, four or five times a day preferably two orthree times a day. In another example, the dosing frequency may be amaximum of five times a day.

Actual dosage levels of active ingredient in the compositions of thepresent invention may be varied so as to obtain an amount of activeingredient that is effective to obtain a desired therapeutic responsefor a particular composition. The formulations of the invention may beadministered as a single dose, or may comprise of a number of smallerdoses, such as two 100 mg dose of LD for a total 200 mg dose, to beadministered or consumed within a short period of time, such as within15 minutes or less, preferably within 10 minutes or less and mostpreferably within 5 minutes of less. It is understood that the precisedosage and duration of treatment is a function of the disease beingtreated and may be determined using known practices. It is to be notedthat dosage values may also vary with the severity of the condition tobe alleviated. It is to be further understood that for any particularsubject, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the formulations ofthe invention, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed compositions. Preferably the doses may be administered 2, 3or 4 times a day (per 24 hour time period), and most preferably 2 or 3times a day.

The LD bioavailability of the dosage forms of the present inventioncompared to an immediate release CD-LD product should be at least 70%,75%, 80%, 85%, 90% or more.

Optimally, after administration to a patient suffering from a conditionassociated with reduced or impaired dopamine levels, a dosage form ofthe invention releases LD into the plasma of the patient at a steady ornear constant level without significant decrease or fluctuation for anextended amount of time, thereby reducing motor fluctuations.

Preferred compositions of the present invention include:

A multiparticulate formulation comprising: a) one or more immediaterelease component(s) comprising LD and/or CD and optionally at least onepharmaceutically acceptable excipient as previously described and b) oneor more controlled release component(s) comprising controlled releasebeads, pellets, tablets, mini-tablets, or granules wherein the beads,pellets, tablets, mini-tablets, or granules comprise a core of LD freeor substantially free of CD and at least one pharmaceutically acceptableexcipient as previously described, a muco-adhesive coating or layerapplied to and/or surrounding the core and an enteric coatingsurrounding the muco-adhesive coating or layer wherein the controlledrelease beads, pellets, tablets, mini-tablets, or granules alsocomprises a controlled release material. The controlled release materialmay be: i) mixed with the LD to form a controlled release matrix core,ii) applied as a coating or layer onto the core comprising the LD and atleast one pharmaceutically acceptable excipient; iii) incorporated ormixed into the muco-adhesive coating or layer or iv) a combination of(i), (ii) and/or (iii). Cosmetic and/or seal coatings as previouslydescribed may also employed in immediate release and controlled releasecomponents of this embodiment.

An alternative preferred compositions includes:

A multiparticulate formulation comprising: a) one or more immediaterelease component(s) comprising of LD, CD and optionally at least onepharmaceutically acceptable excipient as previously described; b) one ormore controlled release component(s) free or substantially free of CDcomprising beads, pellets, mini-tablets or granules wherein the beads,pellets, tablets, mini-tablets or granules comprise a core of LD and atleast one pharmaceutically acceptable excipient as previously described,a muco-adhesive coating or layer applied to and/or surrounding the coreand an enteric coating surrounding the muco-adhesive coating or layerwherein the controlled release beads, pellets, tablets, mini-tablets orgranules also comprises a controlled release material and c) an entericcoated component comprising a plurality of enteric coated beads,pellets, mini-tablets or granules comprising a core comprising LD and/ora decarboxylase inhibitor and at least one pharmaceutically acceptableexcipient as previously described and an enteric coating surrounding thecore. The controlled release material employed in the controlled releasecomponent may be: i) mixed with the LD and at least one pharmaceuticallyacceptable excipient to form a controlled release matrix core, ii)applied as a coating or layer onto the core of the LD and at least onepharmaceutically acceptable excipient; iii) incorporated or mixed intothe muco-adhesive coating or layer or iv) a combination of (i), (ii)and/or (iii). The enteric coated component will release 100% of the LDand/or a decarboxylase inhibitor within 90 minutes, preferably 60minutes and most preferably within 45% when tested using a USP Type I orII apparatus, at 37° C., with a rotational speed of 75 rpms and 900 mlof an aqueous media with a pH between 6.8-7.4. Cosmetic and/or sealcoatings as previously described may also employed in immediate releaseand controlled release components of this embodiment.

EXAMPLES Example 1

I. Development of LDEE-S beads for IPX203-B-12-01

Development of Core LDEE-S Breads

Preparation of Core Beads

Required amounts of LDEE-S-Dihydrate, Microcrystlline Cellulose, Fumaricacid, Povidone K29-32, ethanol and Purified Water were dispensed. Thealcohol and the purified water were charged into a container and stirredusing a stir bar. Povidone was slowly added into the ethanol/water mixedsolvent. Mixing continued until the Povidone was completely dissolved,and the spray pump was calibrated to the target granulation spray rate.

LDEE-S-Dihydrate, Microcrystalline Cellulose, Fumaric acid, and Povidonewere charged into a high shear granulator and dry mixed for 1-5 minutesat impeller speed of 75 rpm and chopper speed of 1000 rpm. The Povidonesolution was sprayed into the granulation bowl and granulation continuedwith either ethanol or water as necessary. The granules were wet mixedfor 2 minutes, after the spraying was completed.

The wet granules were extruded using the extruder (MG 55 MultiGranulator) equipped with a 0.8 mm hole size screen at extruder speed of55 rpm. the extrudates were collected into double polyethylene linedbags. The collected extrudate was weighed and adjusted in the quantitiesranging from 170-210 g per load.

One load of the weighed extrudate was charge into a spheronizer equippedwith a 3 mm cross hatch disc. The extrudate was spheronized at aspheronisation speed of 1400 rpm for 1-10 mins. The spheronized beadswere discharge into double polyethylene bags. The remaining extrudatewere spheronized until all the double polyethylene-lined bags arecompleted.

The wet beads were dried in a fluid bed drier (Glatt GPCP-1) at an Inlettemperature of 35±10° C. until Loss on Drying was not more than 5.0%.The steps above were repeated until additional sub loads had beenprocessed.

The dried beads were passed through a mechanical sieve (Vibroscreen)equipped with a 24-MG mesh screen at the bottom, 18-MG mesh screen inthe middle, and 16-MG mesh screen at the top. The beads that remained on18-US mesh and 24-MG mesh screens were collected into doublepolyethylene lined bags.

Muco-Adhesive/Rate-Controlling Sub-layer Coating

The batch yield was determined. The required amounts of AminoMethacrylate Copolymer (Eudragit® El00) and Talc were calculated anddispensed. Purified Water, Acetone and Isopropyl Alcohol were dispensedinto a stainless steel container and stirred using stir bar. Whilestirring, Amino Methacrylate Copolymer (Eudragit® El00) was slowly addedinto the vortex of the mixed solvent. Mixing continued until thecopolymer completely dissolved. While stirring, Talc was slowly disperseinto the vortex of the solution. Mixing continued until the material wascompletely dispersed. The suspension was continually stirred throughoutthe coating process.

The spray pump was calibrated to the target coating spray rate of theperistaltic pump using the suspension solution above. The core beadswere coated using Glatt GPCG 1 equipped with a Wurster insert at Inletair temperature of 35±10° C., Atomization air pressure of 1.0-2.0 barsand Wurster partition height of 15-30 mm. During coating, the inlet airtemperature, exhaust flap, and spray rate were adjusted to maintain theexhaust air temperature between 30±5° C.

After the target amount of coating solution was sprayed, the coatedbeads were dried at an inlet air temperature of 40±10° C. for 90minutes. The dried beads were passed through a mechanical sieve(Vibroscreen) equipped with a pan at the bottom, 14-MG mesh screen inthe middle, and 12-MG mesh screen at the top. The beads that remained inthe pan and 14-MG mesh screens were collected into double polyethylenelined bags.

Enteric Coating

The batch yield was determined. Based on the batch yield, the requiredamounts of Triethyl Citrate, Talc and an enteric copolymer, eitherMethacrylic Acid Copolymer, Type A, (Eudragit® L100)/Methacrylic AcidCopolymer, Type B, (Eudragit® S) at 1/2 weight ratio for IPX203-C0006 orEudragit® LI00-55 for IPX203-C0004 and IPX203-C0005 were calculated anddispensed. Acetone and Isopropyl Alcohol for IPX203-C0006 or Acetone,Isopropyl Alcohol and purified water for IPX203-C0004 and IPX203-C0005were dispensed into a stainless steel container and stirred using stirbar. While stirring, the enteric copolymer and Triethyl Citrate wereadded slowly into the vortex of the mixed solvent. Mixing continueduntil the copolymer was completely dissolved.

While stirring, Talc was added slowly into the vortex of the solution.Mixing continued until the material was completely dispersed. Thesuspension was continually stirred throughout the coating process. Thespray pump was calibrated to the target coating spray rate of theperistaltic pump using the suspension solution.

Eudragit® E-coated beads were coated with the enteric composition usingGlatt GPCG 1 equipped with a Wurster insert at Inlet air temperature of35±10° C., Atomization air pressure of 1.0-2.0 bars and Wursterpartition height of 15-30 mm. During coating, the inlet air temperature,exhaust flap, and spray rate were adjusted to maintain the exhaust airtemperature between 30±5° C.

After the target amount of coating solution was sprayed, theenteric-coated beads were dried at an inlet air temperature of 40±10° C.for 120 minutes. The dried beads were passed through a mechanical sieve(Vibroscreen) equipped with a pan at the bottom, 14-MG mesh screen inthe middle, and 12-MG mesh screen at the top. The beads that remained inthe pan and 14-MG mesh screens were collected into double polyethylenelined bags.

Encapsulation

The batch yield was determined. Based on the batch yield, the requiredamounts of the enteric coated beads (also referred to herein as beadshaving an outer enteric coating polymer layer) and talc were calculatedand dispensed. The Enteric Coated Beads and Talc were placed in anappropriated sized plastic bag and were manually blended by shaking theplastic bag with the beads and Talc for 10 minutes. The blend wasencapsulated with 00 size gelatin capsules, using MG FlexalabEncapsulator at the target fill weight of 482 mg, 537 mg and 472 mg forIPX203-C0004, IPX203-C0005 and IPX203-C0006 respectively, so that thetarget LDEE dose/2 capsules was 228 mg, equivalent to LD dose of 200 mg.

Rationale for Components and Coatings in Formulation

The core bead formulation was developed utilizing microcrystallinecellulose (MCC) as filler since the wetted MCC has the desiredrheological properties, cohesiveness, and plasticity to yield strongbeads. An MCC level at 30% was selected and it was found to providebeads with acceptable sphericity and support a robust manufacturingprocess. Because LDEE-S is more stable in acidic environment, in orderto reduce the LDEE degradation inside the beads during the long releaseduration, a 5% fumaric acid is added in the formulation to lower themicroenvironment pH. An extra binder povidone at 1% level is also addedto the formulation with the intent to provide a more robust extrusionprocess. The dissolution profile of the core beads is fast, with thecomplete release within 30 min, as measured in a USP Apparatus 1 withbasket speed of 75 rpm in pH 7 phosphate buffer.

To control the release of LDEE-S, the core LDEE-S beads are coated withdifferent release polymers. Eudragit® El00 is swellable and permeableabove pH 5. It is used as an inner coating to slowly release drug atintestinal pH. As such, the use of Eudragit® El00 coating results in acontrolled release of LDEE-S. Furthermore, to protect the Eudragit® Elayer as well as to direct the release of LDEE-S to the more alkalineregion (i.e., intestinal region and not the stomach region), an entericcoating is applied as an outer coat.

Development of Eudragit® El00 Coated LDEE-S Beads

Prototype formulations with different Eudragit® El00 coating contentwere developed and evaluated based on the in vitro dissolution profilesin pH 7 phosphate buffer solution. Analysis of the effect of coatingthickness on LDEE release indicates that increasing the coating leveldecreases the in vitro release of active pharmaceutical ingredient (API)and although polymer has the sustained-release effect, its permeabilityis relatively large, thus a thick coating is required to prepareformulations with longer release duration (T90>5 hr).

In the final polymer coating formulation, talc was also added as alubricant to facilitate the fluid bed coating process at a ratio ofEudragit® El00/talc at 10/1.

Development of Enteric Coating of Eudragit® E100 Coated LDEE-S Beads

Initially, the enteric coating chosen at the development stage wasEudragit® SI00 and LI00 at a ratio of 2:1, and the ratio among polymerand other components was Eudragit® polymer: triethyl citrate (TEC): Talcratio of 7:2:1.

The in vitro dissolution profiles of prototype enteric coated beads(already coated with Eudragit® El00 at a coating level of 65% w/w)coated with different levels of enteric film. The results showed that acoating level of 23% provides an adequate acid protection with less than5% LDEE released in acidic medium. Further, with less enteric coatinglevel (<10%), there is ˜20% LDEE released in acidic medium, and nosignificant difference in drug release profiles when coated at 5% or10%.

When the dissolution was done in pH 1 solution for 2 hr and then switchto pH 7 buffer, even with outer enteric coating layer, the permeabilityof inner Eudragit® El00 layer may increase after 2 hr in pH 1.0 medium,since T90 was around 6.5 hr in pH 7 buffer for Eudragit® E coated beadsbut shortened to ˜4.5 hr in pH 7 buffer for enteric coated beads afterswitch over of dissolution medium.

For IPX203-B12-01, enteric polymer coatings that can dissolve at lowerpH were also developed, in which Eudragit® L100-55 (dissolve above pH5.5) was used instead of Eudragit® SI00 and LI00. The ratio amongpolymer and other components in the coating formulation was Eudragit®LI00-55: TEC: Talc of 6:1:3.

Dissolution Medium pH Effect on LDEE Release from Enteric Coated Beads

The effect of pH on the release of LDEE from the LDEE-S core beadscoated with Eudragit® E (65% w/w) and enteric coat (Eudragit® S100/L100at 2/1) was conducted at pH 1.0 solution for 2 hr and then switch to pH6.6, 6.8, 7.0 buffer solutions.

The results indicated that with less enteric layer coated (10%) orthinner enteric outer coating, drug release was earlier, and conversely,with a thicker enteric outer coating (23%), drug release was delayed atall pH' s compared to the thinner enteric outer coated LDEE-S corebeads. Further, with less or thinner enteric outer coating, there was noeffect on drug release when pH changed from 6.6 to 6.8, and the drugrelease was slower when pH changed to 7.0. However, when thicker entericcoat layer was applied (23%), there was no effect on drug release whenpH changed from 6.8 to 7.0, but the drug release was much slower when pHchanged to 6.6. Additionally, the pH value in dissolution medium canaffect drug release profiles through its effect on both enteric coatinglayer dissolution and Eudragit® E layer permeability. When enteric coatlayer is thin, its dissolution is fast and the pH effect on Eudragit® Eis more a rate-limiting factor. Since Eudragit® E permeability decreaseswith increasing pH, slower release was observed in pH 7.0 medium.However, with a thicker enteric coat, the dissolution of the entericlayer is much slower and become a rate-limiting step. With a combinationof Eudragit® S100 and L100 at a ratio of 2/1, its dissolution at lowerpH (pH 6.6) is much slower than at pH above 6.8. Thus the drug releaseis much slower in pH 6.6 medium with a thicker enteric coating.

Final Formulation of LDEE-S Beads for IPX203-B12-01

The test formulations for IPX203-B12-01 are summarized in Table 1. Thecomposition of the formulations of LDEE-S beads (IPX203-C0004,IPX203-C0005 and IPX203-C0006) is summarized in Table 2. FIG. 2 showsthe in vitro dissolution profiles of those formulations. IPX203-C0066was coated with 10% (w/w) enteric coat (Eudragit® S100/L100 at 2/1),which released ˜20% drug in the first 2 hr in pH 1.0 solution. Afterdissolution medium switch to pH 7 buffer, drug was controlled releasedover a period T90˜3hr. A better acidic protection for IPX203-0004 andIPX203-C0005 was observed due to their thicker enteric coat layer (25%w/w, Eudragit® L100-55). Formulations IPX203-C0004 has a thinnerEudragit® El00 layer of coating compared to IPX203-C00005, and hasT90˜3hr in pH 7 buffer. IPX203-C0005 provided longer release duration(T90˜5hr in pH 7 buffer).

TABLE 1 Test Formulations of IPX203 Prototype Capsule in Single DoseRelative Bioavailability (BA) Studies IPX203-B12-01*. Test FormulationStudy LDEE (mg/2 capsules) IPX203-C0004 IPX203-B12-01 228 IPX203-C0005228 IPX203-C0006 228 *Carbidopa was dosed as commercial productLodosyn ® 25 mg/tablet with the dosing regimen: 25 mg at T = 0 and 6.25mg (1/4 tablet) at T = hr.

TABLE 2 Composition of Final Formulation of LDEE-S Beads forIPX203-B12-01 Composition (w/w %) IPX203- IPX203- IPX203- IngredientC0004 C0005 C0006 Levodopa Ethyl Ester Succinate, 31.76 28.50 32.39Dihydrate Microcrystalline Cellulose, NF 14.66 13.15 14.95 Fumaric Acid,NF 2.44 2.19 2.49 Povidone, USP (Plasdone, K-29/32) 0.49 0.44 0.50 AminoMethacrylate Copolymer, NF 27.14 31.74 36.08 (Eudragit ® E 100)Methacrylic Acid Copolymer, Type 11.88 11.88 — C, NF (Eudragit ®L100-55) Methacrylic Acid Copolymer, Type — — 2.10 A, NF (Eudragit ® L100) Methacrylic Acid Copolymer, Type — — 4.20 B, NF (Eudragit ® S 100)Triethyl Citrate, NF 1.98 1.98 1.80 Talc, USP 9.64 10.12 5.50 Total100.0 100.0 100.0

II. In Vivo Results of IPX203-B12-01

The in vivo performance of the prepared formulations IPX203-C0004,IPX203-C0005 and IPX203-C0006 has been evaluated in healthy volunteersin a relative bioavailability analysis of IPX203-B12-01. The studydesign was a randomized, single-dose, crossover study in normal, healthyvolunteers under fasting condition.

FIG. 3 shows the plasma profile for the multi-particulate formulationsIPX203-C0004, IPX203-C 0005 and IPX203-C0006 in comparison with Sinemet®CR. All the IPX 203 multi-10 particulate formulations comprise Eudragit®E coating. The relative bioavailability parameters are provided in Table3. Comparison of the LD plasma concentration profile of the testedformulations to the reference product Sinemet® CR indicate that bothIPX203-C0005 and IPX203-C0006 showed sufficient AUC but more extendedeffect than Sinemet® CR, Further, the difference of Tmax betweenIPX203-C0004 and IPX203-C0005 corresponds well with their difference inin vitro dissolution profiles. Also, although the in vitro releaseprofiles for IPX203-C0004 and IPX203-C 0006 showed similar T90 (˜3hr)after switch to pH 7 buffer, IPX203-C0006 showed more delayed effect invivo. Additionally, the results show that IPX203-C0006 has Cmax and AUCcomparable to those of Sinemet® CR.

TABLE 3 Relative LD Bioavailability Parameters of IPX203 Capsules Testedin Bioavailability Analysis of IPX203-B12-01 (n = 15). % Ratio ofDuration LD Test CD-LDEE(mg)^(a) Test/Sinemet ® CR Concentration >Formulation LDEE CD AUC0-∞ Cmax 50% Cmax (h)^(b) IPX203-C0004 228 31.2580  86 2.9 (3.3) IPX203-C0005 228 97  97′ 3.15 (3.25) IPX203-C0006 22887 104 3.25 (3.25) ^(a)LDEE 228 mg is equivalent to LD 200 mg.^(b)Sinemet ® CR tablet t_(max) = 2.5 hr

Example 2

I. Processing Procedures for Levodopa Ethyl Ester Succinate(LDEE-S)/Carbidopa (CD) Capsules for IPX203 B13-01

Preparation of Core Beads for IPX203-C0012, IPX203-C0013 andIPX203-C0016

Required amounts of LDEE-S-Dihydrate, Microcrystalline Cellulose,Fumaric acid, Povidone K29-32, ethanol and Purified Water weredispensed. The alcohol and the purified water were charged into acontainer and stirred using stir bar, Povidone was slowly added into theethanol/water mixed solvent. Mixing continued until the Povidone wascompletely dissolved, and the spray pump was calibrated to the targetgranulation spray rate.

LDEE-S-Dihydrate, Microcrystalline Cellulose, Fumaric acid, and Povidonewere charged into a high shear granulator and dry mixed for 1-5 minutesat impeller speed of 75 rpm and chopper speed of 1000 rpm. The Povidonesolution was sprayed into the granulation bowl and granulation continuedwith either ethanol or water as necessary. The granules were wet mixedfor 2 minutes, after the spraying was completed.

The wet granules were extruded using the extruder (MG 55 MultiGranulator) equipped with a 0.8 mm hole size screen at extruder speed of55 rpm. The extrudates were collected into double polyethylene-linedbags. The collected extrudate was weighed and adjusted in the quantitiesranging from 180-240 g per load.

One load of the weighed extrudate was charge into a spheronizer equippedwith a 3 mm cross hatch disc. The extrudate was spheronized at aspheronisation speed of 1400 rpm for 1-10 mins. The spheronized beadswere discharge into double PE bags. The remaining extrudate werespheronized until all the double polyethylene-lined bags are completed.

The wet beads were dried in a fluid bed drier (Glatt GPCP-1) at an Inlettemperature of 35±10° C. until Loss on Drying is not more than 5.0%. Thesteps above were repeated until additional sub loads have beenprocessed.

The dried beads were passed through a mechanical sieve (Vibroscreen)equipped with a 24-MG mesh screen at the bottom, 18-MG mesh screen inthe middle, and 16-MG mesh screen at the top. The beads that remained on18-US mesh and 24-MG mesh screens were collected into doublepolyethylene-lined bags.

Rate-Controlling Membrane Coating for IPX203-C0012 and IPX203-C0013

IPX203-C0012 Beads

Batch yield was determined. Based on the batch yield, the requiredamounts of Cellulose Acetate (CA) and Polyethylene Glycol 3350 (PEG3350)at weight ratio (CA/PEG) of 95/5 and Acetone/Purified Water (95/5 w/w)were calculated and dispensed. The Acetone was dispensed into astainless steel container and stirred using stir bar. While stirring,Cellulose Acetate (CA) was added slowly into the vortex of the solventand mixing was continued until the copolymer completely dissolved.

The Purified Water was dispensed into another stainless steel containerand was stirred using a stir bar. While stirring, Polyethylene Glycol3350 (PEG3350) was added slowly into the vortex of the purified watersolvent and mixing was continued until the copolymer completelydissolved. While stirring, PEG solution was added quickly into the CAsolution and mixing was continued until the solution was clear. Spraypump was calibrated to the target coating spray rate of the peristalticpump using the clear solution and the core beads were coated using GlattGPCG 1 equipped with a Wurster insert at Inlet air temperature of 33±10°C., Atomization air pressure of 1.0-2.0 bars and Wurster partitionheight of {circumflex over ( )}0-40 mm. During coating, the inlet airtemperature, exhaust flap, and spray rate were adjusted to maintain theexhaust air temperature between 30±5° C.

After the target amount of coating solution was sprayed, the coatedbeads were dried at an inlet air temperature of 35±10° C. for 40-60minutes. The dried beads were passed through a mechanical sieve(Vibroscreen) equipped with a pan at the bottom and a 14-MG mesh screenat the top. and collected the beads that passed through the 14-MG meshscreen were collected in double polyethylene-lined bags. Oversized beadsthat remained on the 14-MG mesh screen were rejected.

IPX203-C0013 Beads

The procedure for preparing the coating solution and the coatingconditions are identical to those for IPX203-C0012 coating. However, therate-controjling polymer is Cellulose Acetate (CA), and the solvent isAcetone.

Muco-Adhesive Coating for IPX203-C0012, IPX203-C0013 and IPX203-C0016

The batch yield was determined. The required amounts of AminoMethacrylate Copolymer (Eudragit® El00) and Talc were calculated anddispensed at weight ratio of 91/9. Purified Water, Acetone and IsopropylAlcohol were dispensed at weight ratio of 12/68/20 into a stainlesssteel container and stirred using stir bar. While stirring, AminoMethacrylate Copolymer (Eudragit® E100) was slowly added into the vortexof the mixed solvent. Mixing continued until the copolymer completelydissolved. While stirring, Talc was slowly dispersed into the vortex ofthe solution. Mixing continued until the material was completelydispersed. The suspension was continually stirred throughout the coatingprocess.

The spray pump was calibrated to the target coating spray rate of theperistaltic pump using the suspension solution above. Therate-controlling membrane-coated beads for IPX203-C0012 andIPX203-C0013, or the core beads for IPX203-C0016 were coated with themuco-adhesive coating composition Glatt GPCG 1 equipped with a Wursterinsert at Inlet air temperature of 35±10° C., Atomization air pressureof 1.0-2.0 bars and Wurster partition height of 15-40mm. During coating,the inlet air temperature, exhaust flap, and spray rate were adjusted tomaintain the exhaust air temperature between 30±10° C.

After the target amount of coating solution was sprayed, the coatedbeads were dried at an inlet air temperature of 40±10° C. for 60-120minutes. The dried beads were passed through a mechanical sieve(Vibroscreen) equipped with a pan at the bottom and a 14-MG mesh screenat the top. The beads that passed through 14-MG mesh screen werecollected into double polyethylene-lined bags and the oversized beadsthat remained on the 14-MG mesh screen were rejected.

Enteric Coating for IPX203-C0012, IPX203-C0013 and IPX203-C0016

The batch yield was determined. Based on the batch yield, the requiredamounts of Triethyl Citrate, Talc and an enteric copolymer, eitherMethacrylic Acid Copolymer, Type A, (Eudragit L100)/Methacrylic AcidCopolymer, Type B, (Eudragit® S) at 1/2 weight ratio for IPX203-C0012and IPX203-C0016 or Eudragit® L100 for IPX203-C00013 were calculated anddispensed. Acetone and Isopropyl Alcohol were dispensed at weight ratioof 40/60 into a stainless steel container and stirred using stir bar.While stirring, the enteric copolymer and Triethyl, Citrate (TEC) wereadded slowly into the vortex of the mixed solvent and mixing wascontinued until the enteric copolymer completely dissolved. Whilestirring, Talc was slowly dispensed into the vortex of the solution andmixing was continued until the material was completely dispersed. Thesuspension was continuously stirred throughout the coating process. Theweight ratio of enteric copolymer/TEC/Talc was 70/20/10.

The spray pump was calibrated to the target coating spray rate of theperistaltic pump using the solution, and the Eudragit® E-coated beadswere coated using Glatt GPCG 1 equipped with a Wurster insert at Inletair temperature of 35±10° C., Atomization air pressure of 1.0-2.0 barsand Wurster partition height of 15-30mm. During coating, the inlet airtemperature, exhaust flap, and spray rate were adjusted to maintain theexhaust air temperature between 30±5° C. After the target amount ofcoating solution was sprayed, the coated beads were dried at an inletair temperature of 40±10° C. for 60-120 minutes and the dried beads werepassed through a mechanical sieve (Vibroscreen) equipped with a pan atthe bottom and a 14-MG mesh screen at the top. The beads that passedthrough 14-MG mesh screen were collected into double polyethylene-linedbags, and oversized beads that remained on the 14-MG mesh screen wererejected.

Immediate Release Granules (CD/LDEE-S)

The required amount of 27% Carbidopa USP, 49.9% Levodopa Ethyl EsterSuccinate-Dihydrate, 12.2% Dibasic Calcium Phosphate Anhydrous, 7.0%Hydroxypropyl Cellulose (Klucel-EXF), and 2.0% Croscarmellose Sodium,(Ac-Di-Sol) were dispensed and charged into the granulation bowl of ahigh shear granulator. The components were dry-mixed for 1-3 mins atimpeller speed between 150-250 rpm and Chopper Speed of 1000 rpm.Purified Water was sprayed at a desired flow rate into the granulationbowl until consistent wet mass was reached. The water/dry blend weightratio was between 0.20-0.40. The granules were wet-mixed for additional1-5 minutes, after the spraying was completed. The wet granules werecharged into the top spray product bowl of GPCG1 and dried using GPCG 1at inlet air temperature of 50° C. until the LOD is less than 6.0%.Inlet air flow was adjusted to maintain the fluidization of the wetgranules. The dried granules from the bowl were transferred into clean,double polyethylene-lined containers, and the granules were passedthrough the Fitzmill equipped with a stainless steel #24 mesh screen atKnife Mode and speed of 2000-3000 rpm. The required amount of Talc wascalculated based on the weight of the milled granules and 2% Talc of theimmediate release granules. The milled granules and Talc were chargedinto Pharmatech Miniblender and blended for 5 minutes. The blend wasdischarged into clean, double polyethylene-lined containers.

Encapsulation

The batch yield was determined. Based on the batch yield, the requiredamounts of the Enteric Coated Beads and Talc (at weight ratio of 99/1)were calculated and dispensed. The Enteric Coated Beads and Talc werecharged into an appropriated sized plastic bag and manually blended byshaking the plastic bag for 10 minutes. The blend and Immediate ReleaseGranules (CD/LDEE-S) were encapsulated with 00 size gelatin capsules,using MG Flexalab Encapsulator. For IPX203-C 0016, the blend wasencapsulated but the Immediate Release Granules (CD/LDEE-S) were not.Table 4 shows the target fill weight for IPX203-C0012, IPX203-C0013 andIPX203-C0016 and Table 5 lists the composition of IPX203-C0012,IPX203-C0013 and IPX203-C0016.

TABLE 4 Target Fill Weight of IPX203-C0012, IPX203-C0013and IPX203-C0016Target Fill Weight (mg/Capsule) Enteric-coated Beads Immediate releaseGranules IPX203-C0012 389.5 200.0 IPX203-C0013 412.0 200.0 IPX203-C0016252.6 N/A

TABLE 5 Formulation Composition of IPX203-C0012, IPX203-C0013 andIPX203-C0016 IPX203-00012 1PX203-00013 IPX203-00016 Amount % Amount %Amount % Ingredient (mg/capsule) (w/w) (mg/capsule) (w/w) (mg/capsule)(w/w) Carbidopa, USP 54.0 9.2 54.0 8.8 Levodopa Ethyl Ester Succinate,306.4 52.0 306.4 50.1 81.8 32.4 Dihydrate Microcrystalline Cellulose, NF95.4 16.2 95.4 15.6 37.7 14.9 Amino Methacrylate Copolymer, 33.1 5.633.4 5.5 91.1 36.1 NF (Eudragit ® E100) Fumaric Acid, NF (Fine Granules)15.9 2.7 15.9 2.6 6.3 2.5 Cellulose Acetate, NF 9.1 1.5 12.9 2.1 0.0(CA-398-10 NF) Talc, USP 13.1 2.2 15.2 2.5 13.9 5.5 Methacrylic AcidCopolymer, Type 8.5 1.4 10.6 4.2 B, NF (Eudragit ® S100) MethacrylicAcid Copolymer, Type 4.3 0.7 25.9 4.2 5.3 2.1 A, NF (Eudragit ® L100)Triethyl Citrate, NF 3.7 0.6 7.4 1.2 4.5 1.8 Povidone, USP (Plasdone,3.2 0.5 3.2 0.5 1.3 0.5 K-29/32) Polyethylene Glycol, NF 0.5 0.1 DibasicCalcium Phosphate, 24.3 4.1 24.3 4.0 Anhydrous Hydroxypropy Cellulose,NF 14.0 2.4 14.0 2.3 (Klucel-EXF) Croscarmellose Sodium, NF 4.0 0.7 4.00.7 (Ac- Di-Sol) Total 589.5 100.0 612.0 100.0 252.6 100.0 *54 mg ofCarbidopa, USP is equivalent to 50 mg of Carbidopa anhydrate. **306 mgof Levodopa Ethyl Ester Succinate-Dihydrale is equivalent to 228 mg ofLevodopa Ethyl Ester and to 200 mg Levodopa.

II. Processing Procedures for Manufacturing Entacapone Capsules forIPX203 B13-01

Preparation of Core Beads for IPX203-C0014 Capsule

The required amount of Entacapone, Microcrystalline Cellulose, PovidoneK29-32 and Purified Water were dispensed. The purified water was chargedinto a container and stirred using a stir bar, the Povidone (1.0% of thesolid blend) slowly added into the water at Povidone/Water weight ratioof 6/133.2 and mixing continued until the Povidone was completelydissolved. The spray pump was calibrated to the target granulation sprayrate (23 g/min), and 84.0% Entacapone and 15.0% MicrocrystallineCellulose were charged into a high shear granulator and were dry mixedfor 1-5 minutes at impeller speed of 200-300 rpm and chopper speed of1400-1600 rpm. The solution was sprayed into the granulation bowl untilall the solution was sprayed, and granulation was continued withPurified Water as necessary. The granules were wet-mixed for 2 minutes,after the spraying was completed. Then the wet granules were extrudedusing the extruder (MG 55 Multi Granulator) equipped with a 0.8 mm holesize screen at extruder speed of 50 rpm. The extrudates were collectedinto double polyethylene-lined bags. Further, the collected extrudatewere weighed and adjusted in the quantities ranging from 200-210 g perload.

One load of the weighed extrudate was charged into a spheronizerequipped with a 3 mm cross hatch disc and spheronized at spheronisationspeed of 1000 rpm for 1-2 mins. The spheronized beads were dischargedinto double PE bags. The wet beads were dried in a fluid bed drier(Glatt GPCP-1) at an Inlet temperature of 35±10° C. until Loss on Dryingwas not more than 5.0%. The dried beads were passed through a mechanicalsieve (Vibroscreen) equipped with a pan at the bottom, 24-MG mesh screenin the middle, and 16-MG mesh screen at the top. The beads that wereretained on 24-MG mesh were collected into double polyethylene-linedbags, and the beads on the pan and 16-MG mesh screen were rejected.

Enteric Coating for IPX203-C0014

The required amounts of Triethyl Citrate, Talc, Methacrylic AcidCopolymer Dispersion, NF (Eudragit® L30D-55) and Water were calculatedand dispensed. The Purified Water was dispensed into a stainless steelcontainer and stirred using a stir bar. While stirring, Triethyl Citrate(TEC¹), Talc and the enteric copolymer dispersion were slowly added intothe vortex of Purified Water, and mixing was continued until thematerial was completely dispersed. The suspension was stirred throughoutthe coating process. The weight ratio of enteric copolymer/Talc/TEC was63.0/30.7/6.3.

The spray pump was calibrated to the target coating spray rate of theperistaltic pump using the solution, and the core beads were coatedusing Glatt GPCG 1 equipped with a Wurster insert at Inlet airtemperature of 35±10° C., Atomization air pressure of 1.0-2.0 bars andWurster partition height of 15-30mm. During coating, the inlet airtemperature, exhaust flap, and spray rate were adjusted to maintain theexhaust air temperature between 30±5° C.

After the target amount of coating solution was sprayed, the coatedbeads were dried at an inlet air temperature of 30±10° C. until themoisture level was below 5%. The dried beads were passed through amechanical sieve (Vibroscreen) equipped with a pan at the bottom and a12-MG mesh screen at the top. The beads that passed through the 12-MGmesh screen were collected into double polyethylene-lined bags, and theoversized beads that remained on the 12-MG mesh screen were rejected.

Encapsulation for IPX203-C0014

The required amounts of the Enteric Coated Beads and Talc (at weightratio of 99/1) were calculated and dispensed, and the Enteric CoatedBeads and Talc were charged into an appropriate sized plastic bag. Thebeads and Talc were manually blended by shaking the plastic bag for atleast 5 minutes. The blend was encapsulated with 00 size gelatincapsules, using MG Flexalab Encapsulator. The target fill weight was 505mg. Table 6 lists the composition of IPX203-C0014.

TABLE 6 Formulation Composition of Entacapone Capsule (IPX203-00014)Amount Ingredient % (w/w) (mg/capsule) Entacapone 79.2 400.0 Microcrystalline Cellulose, NF 14.1 71.4  (Avicel PH-101) Povidone, USP(Plasdone, K-29/32) 1.0 4.8 Methacrylic Acid Copolymer Dispersion, 3.015.0  NF (Eudragit ® L30D-55) Talc, USP 2.4 12.3  Triethyl Citrate, NF0.3 1.5 Total 100.0  505.0 

III. In Vitro Release Profiles of Final LE(EE-S-Dihydrate Dosage Formsfor Pharmacokinetic (IPX203-B13-01)

Table 7 lists the test regimen for the 5-arm cross-over PK analysis(IPX203 B13-01).

TABLE 7 Dosing Regimen for IPX203 B13-01 CD/ LD/ Entacaponc/ RegimenDosage Form capsule capsule capsule Regimen A IPX203-C0012   50 mg   200mg* N/A Regimen B IPX203-C0012 + IPX203-C0014   50 mg   200 mg* 400 mgRegimen C IPX203-C0013 + IPX203-C0014   50 mg   200 mg* 400 mg Regimen D  IPX203-C0013 + IPX203-C0016 +   50 mg 255.6 mg* 400 mg IPX203-C0014Regimen E Stalevo ® 150 mg 37.5 mg  150 mg 200 mg *LD equivalent dosebased on total amount of LDEE-S-Dihydrate in the formulation

The in vitro release profiles of the regimen A-D were measured using USPI dissolution method at agitation speed of 75 rpm in Simulated GastricFluid (pH 1.0) for first 2 hrs and followed by in Simulated IntestinalFluid (pH 7.0). FIG. 4 shows the release profiles of these testregimens.

The T90 (time duration for 90% of LDEE-S-Dihydrate released) isapproximately 3 hr, 4.5 h and 6hrs for Regimen B, C and D, respectively.The LDEE-S-Dihydrate capsule (C0012) was used in both Regimen A andRegimen B.

VI. In Vivo Evaluation (IPX203-B13-01)

The in vivo performance of the prepared dosage forms IPX203-C00012,IPX203-C00013 and IPX203-C00014 and IPX203-C0016 has been evaluated in12 healthy volunteers under fasted condition in a relativebioavailability analysis of IPX203-B13-01. The four test treatmentswere:

Regimen A: C0012

Regimen B: C0012+C0014

Regimen C: C0013+C0014

Regimen D: C0013+C0016+C0014

Regimen E: Stalevo 150 (Reference)

Where

C0012 contained 228 mg LDEE ER beads with T90-3 hrs and 50 mg CD

C0013 contained 228 mg LDEE ER beads with T90-5 hrs and 50 mg CD

C0014 contained 400 mg enteric-coated entacapone

C0016 contained 77 mg LDEE ER beads with T90-12 hrs

FIG. 5 shows the levodopa plasma profiles for all these regimens. Basedon the in vivo plasma profiles depicted in FIG. 5 , the in vivo plasmaprofiles correlates well with the in vitro dissolution profiles depictedin FIG. 4 . FIG. 5 demonstrates that Regimen D has the longesttherapeutic coverage and a constant plasma profile.

Example 3

Prepared Carbidopa Beads

The core beads of CD beads were formulated based on thegranulation-extrusion-spheronisation technology. 30 w/w % MCC was usedin the core seed formulation. No controlled release coating layer wasneeded. CD core beads was enteric-coated with the enteric coatingformulation comprising EUDRAGIT® SI00 and LI00 at a ratio of 2:1. Theenteric coating level was 5%.

Table 8 summarized the composition of final formulation of CD beads.

TABLE 8 Composition of Formulation of CD Beads Ingredient Composition(w/w %) Carbidopa 66.44 Microcrystalline Cellulose, NF 28.47 MethacrylicAcid Copolymer,  1.14 Type A, NF (Eudragit ® L 100) Methacrylic AcidCopolymer,  2.35 Type B, NF (Eudragit ® S 100) ′ Triethyl Citrate, NF 1.00 Talc, USP  0.60 Total 100.0 

Example 4

The preparation procedure in Example 1 was repeated in this example,except the coating compositions. The core beads were coated first witheither cellulose acetate polymer or a combination of Hypromellose andethylcellulose. The coated beads were further coated with chitosan orpolycarbophil or Eudragit® El00. After the second layer coating, thebeads were further coated with Eudragit® L100-55. Table 9 shows thecomposition of four formulations IPX203-C0007, IPX203 -C0008, IPX203-C0009 and IPX203 -C0010.

TABLE 9 Composition of Formulations of LDEE-S Beads Using Chitosan orPolycarbophilas Muco-adhesive Polymers Composition (w/w %) IPX203-IPX203- IPX203- IPX203- Ingredient C0007 C0008 C0009 C0010 LevodopaEthyl Ester Succinate, Dihydrate 39.45 45.18 31.14 45.30Microcrystalline Cellulose, NF 18.21 20.85 14.37 20.91 Fumaric Acid, NF 3.03  3.48  2.40  3.48 Povidone, USP (Plasdone, K-29/32)  0.61  0.70 0.48  0.70 Hypromellose, Type 2910, USP  2.82 —  2.23  4.22 (Pharmacoat606, 6 cps) Ethylcellulose, NF (Ethocel, 11.28 —  8.90 16.89 Standard-10FP Premium) Polycarbophil, USP (Noveon ® AA-1)  3.77 — —  4.57 CelluloseAcetate, NF (CA-398-10 NF) —  4.21 — — Chitosan, NF (ChitoPharm ® S) — 3.74 — — (Material #50222178) Glacial Acetic Acid, USP —  1.01 — —Amino Methacrylate Copolymer, NF — — 17.86 — (Eudragit ® E 100)Methacrylic Acid Copolymer, 11.91 11.91 11.90  1.76 Type C, NF(Eudragit ® L100-55) Triethyl Citrate, NF (PG)  1.99  1.99  1.98  0.29Talc, USP  6.94  6.93  8.73  1.87 Total 100.0  100.0  100.0  100.0 

Example 5

I. Formulations for IPX203-B14-01 Biostudy

Four test formulations were evaluated in biostudy IPX203-B14-01. ForIPX203-C0023, -C0024, and -C0025 formulations, there were two componentsin one capsule. For IPX203-C0026, there were three components in onecapsule. Table 10 below showed the formulation information for eachproduct, and Tables 11-13 showed formulation composition for eachcomponent.

TABLE 10 Test Formulations for Relative Bioavailability StudyIPX203-B14-01 Entacapone Component II: (ENT) Test Component I: IR LD ERComponent Formulation CD (mg) LD (mg) Prototype/LD (mg) ENT (mg)IPX203-C0023 50 80  Prototype I/280  0 1PX203-C0024 Prototype III/280 IPX203-C0025 Prototype II/280 IPX203-C0026 Prototype II/280 200Stalevo ® 100 CD/LD/ENT (25/100/200 mg) (Reference)

TABLE 11 Composition of Prototype Formulations of IPX203 Component IIComposition (%) Ingredient Prototype I Prototype II Prototype III Corebead levodopa 65.26 62.15 61.03 Microcrystalline Cellulose  8.82  8.40 8.25 Mannitol,  8.82  8.40  8.25 Sodium Lauryl Sulfate  4.41  4.20 4.12 Povidone  0.88  0.84  0.82 CA/Copovidone layer (1^(st) layer)Cellulose Acetate —  1.89  1.85 Copovidone —  2.31  2.27 Eudragit ® E100layer (2^(n<l) layer) Eudragit ® E100  6.42  6.41  3.93 Talc  0.63  0.65 0.40 Enteric layer (3^(rd) layer) Eudragit ® L100  3.34  3.33  6.36Triethyl Citrate  0.96  0.95  1.81 Talc  0.47  0.48  0.91 Total 100.0 100.0  100.0 

TABLE 12 Composition for Component I Formulation Ingredient Composition(w/w %) Carbidopa 35.86 Levodopa 53.14 Croscarmellose Sodium  7.00Povidone  3.00 Magnesium Stearate  1.00 Total 100.0 

TABLE 13 Formulation Composition for Entacapone Component Ingredient %(w/w) Entacapone 73.15 Microcrystalline Cellulose, 14.25 NF (AvicelPH-101) Povidone, USP (Plasdone, K-29/32)  1.90 Sodium Starch Glycolate 3.80 Sodium Lauryl Sulfate, NF  1.90 Methacrylic Acid Copolymer,  3.50Type A, NF (Eudragit ® LI00) Talc, USP  0.50 Triethyl Citrate, NF  1.00Total 100.0 

II. Processing Procedures for Manufacturing IPX203 Capsules for IPX203B14-01 Biostudy

Preparation of Component I

Povidone was dissolved in the purified water completely, and then thespray pump with povidone solution was calibrated to the targetgranulation spray rate (40 mL/min). CD, LD, Croscarmellose Sodium werecharged into a high shear granulator and dry mixed for 1 -5 minutes atimpeller speed of 150 rpm and chopper speed of 1800 rpm. While continuemixing, the solution from Step 1 was sprayed into the granulation bowluntil all the solution is sprayed, and granulation was continued withpurified water if necessary. The granules were collected, and the wetgranules were dried in a fluid bed drier (Glatt GPCP-1) at an Inlettemperature of 65° C. until Loss on Drying is not more than 2.5%. Thedried granules were passed through Fitzmill, and the material thatpasses through 30 mesh screen was collected. The collected material wasblended with magnesium stearate.

Alternative Preparation of Carbidopa-Containing Granules or Beads

In order to avoid potential carbidopa degradation during wet granulationprocess, a dry granulation process by roller compaction was developed.In this formulation, shown in Table 14, the procedures are described asbelow.

Appropriate amount of carbidopa, levodopa, microcrystalline cellulose,and croscarmellose sodium were charged into a suitable mixer. Thematerials were dry mixed for an appropriate time and then charged intoroller compactor at the controlled speed to start the roller compactionprocess. After roller compaction, the collected compacted sheets ofmaterials were blended with colloidal silicon dioxide for appropriatetime, and then milled into dried granules using a suitable mill. Finallythe milled granules were blended with magnesium stearate in the blender.

TABLE 14 Composition for Levodopa/Carbidopa IR Granules by DryGranulation Method Ingredient Composition (w/w %) Carbidopa 37.0 Levodopa 35.0  Microcrystalline Cellulose 20.0  Croscarmellose Sodium4.0 Colloidal Silicon Dioxide i 3.0  Magnesium Stearate 1.0 Total 100.0 

The amount and ratio of carbidopa and levodopa may be adjusted asdesired, so long as performance of the dried granules or beads are notcompromised.

Similarly, controlled release beads containing carbidopa may be preparedby a dry granulation method as provided through the incorporation ofrate-controlling excipient, muco-adhesive polymer, and/or enteric coat.Entacapone-containing beads or granules may also be prepared by a drygranulation method.

Preparation of Component II

Preparation of Core Beads for Component II

Povidone was dissolved in the purified water completely, and thencalibrate the spray pump with povidone solution to the targetgranulation spray rate (18 mL/min). LD, Microcrystalline Cellulose,Mannitol and Sodium Lauryl Sulfate were charged into a high sheargranulator and dry mixed for 1-5 minutes at impeller speed of 250 rpmand chopper speed of 1800 rpm. The solution from Step 1 was sprayed intothe granulation bowl until all the solution is sprayed, and granulationwith purified water was continued as necessary. The wet granules wereextruded using the extruder (MG 55 Multi Granulator) equipped with a 0.9mm hole size screen at extruder speed of 75 rpm. The extrudates werecollected, and the extrudates so collected were charged into aspheronizer equipped with a 3 mm cross hatch disc. The extrudates werespheronized at speed of 800 rpm for 1-2 mins. The wet beads were driedin a fluid bed drier (Glatt GPCP-1) at an Inlet temperature of 65±10° C.until Loss on Drying is not more than 2.5%. The dried beads were passedthrough a mechanical sieve (Vibroscreen) equipped with a 24-MG meshscreen at the bottom, and 16-MG mesh screen at the top. The beads thatremained on the 24-MG mesh screens were collected into doublepolyethylene-lined bags, and the oversized and undersized beads werediscarded.

CA/Copovidonc Layer Coating (for Prototype 11 and III for Component II)

Cellulose acetate and copovidone (Kollidon VA64) were dissolved into themixture of acetone and isopropyl alcohol (IPA) solution (acetone/IPA atweight ratio of 4/1) completely. The pump was calibrated and set at thetarget spray rate of 15 g/min for the coating. The core beads from abovewere coated using Glatt GPCG 2 equipped with a Wurster insert at Inletair temperature of 35° C., Atomization air pressure of 2.0 bars andWurster partition height of 30 mm. During coating, the inlet airtemperature and spray rate were adjusted to maintain the exhaust airtemperature between 25±5° C. After the target amount of coating solutionwas sprayed, the coated beads were dried at an inlet air temperature of35° C. for 30 minutes. The dried beads were passed through a mechanicalsieve (Vibroscreen) equipped with a pan at the bottom and a 14-MG meshscreen at the top. The beads that passed through 14-MG mesh screen werecollected and the pversized beads were rejected.

Eudragit® El00 Layer Coating

Acetone, IPA and purified water (at weight ratio acetone/IPA/water of68/20/12) were dispensed into a stainless steel container and beginstirring using stir bar. While stirring, Triethyl citrate, AminoMethacrylate Copolymer (Eudragit® El00) were slowly added into thevortex of the mixed solvent. The mixing was continued until thecopolymer completely dissolved. While stirring, Talc was slowlydispersed into the vortex of the solution. Mixing was continued untilthe material completely dispersed. The suspension was stirred throughoutthe coating process. The spray pump was calibrated to the target coatingspray rate (10 g/min) using the solution above. The beads (fromPrototype I, and Prototype 11′ and III) were coated using Glatt GPCG 2equipped with a Wurster insert at Inlet air temperature of 33° C.,Atomization air pressure of 2.0 bars and Wurster partition height of 30mm. During coating, the inlet air temperature and spray rate wereadjusted to maintain the exhaust air temperature between 26±5° C. Afterthe target amount of coating solution was sprayed, the coated beads weredried at an inlet air temperature of 35° C. for 30 minutes. The driedbeads were passed through a mechanical sieve (Vibroscreen) equipped witha pan at the bottom and a 14-MG mesh screen at the top. The beads thatpassed through 14-MG mesh screen were collected, and the oversized beadswere rejected.

Enteric (Eudragit® LI00) Coating

Acetone and Isopropyl Alcohol were dispensed at weight ratio of 40/60into a stainless steel container and stirred using a stir bar. Whilestirring, the enteric copolymer Eudragit® LI00 and Triethyl Citrate(TEC) were slowly added into the vortex of the mixed solvent. Mixing wascontinued until the enteric copolymer completely dissolved. Whilestirring, Talc was slowly dispersed into the vortex of the solution.Mixing continued until the material was completely dispersed. Thesuspension was continually stirred throughout the coating process. Thespray pump was calibrated to the target at a coating spray rate (9g/min) using the solution above. The Eudragit® E-coated beads werecoated using Glatt GPCG 2 equipped with a Wurster insert at Inlet airtemperature of 35° C., Atomization air pressure of 2.0 bars and Wursterpartition height of 30 mm. During coating, the inlet air temperature,and spray rate was adjusted to maintain the exhaust air temperaturebetween 27±5° C. After the target amount of coating solution wassprayed, the coated beads were dried at an inlet air temperature of 38°C. for 30 minutes. The dried beads were passed through a mechanicalsieve (Vibroscreen) equipped with a pan at the bottom and a 14-MG meshscreen at the top. The beads that passed through 14-MG mesh screen werecollected, and the oversized beads were rejected.

Preparation of Entacapone Component (for IPX203-C0026)

Povidone was completely dissolved in the purified water. Entacapone,Sodium Starch Glycolate, Sodium Lauryl Sulfate and MicrocrystallineCellulose were charged into a high shear granulator and dry mix for 1-5minutes at impeller speed of 200-300 rpm and chopper speed of 1400-1600rpm. The solution was sprayed into the granulation bowl at the sprayrate of 19 ml/min until all the solution is used, and granulationcontinued with Purified Water as necessary. The wet granules wereextruded using the extruder (MG 55 Multi Granulator) equipped with a 0.9mm hole size screen at extruder speed of 55 rpm. The extrudates werecollected, and charged into a spheronizer equipped with a 3 mm crosshatch disc. The extrudate were spheronized at a spheronization speed of650 rpm for 2 mins. The wet beads were dried in a fluid bed drier (GlattGPCP-1) at an Inlet temperature of 40±5° C. until Loss on Drying is notmore than 5.0%. The dried beads were passed through a mechanical sieve(Vibroscreen) equipped with a pan at the bottom, 24-MG mesh screen inthe middle, and 16-MG mesh screen at the top. The beads that wereretained on 24-MG mesh were collected and the beads on the pan and 16-MGmesh screen were rejected. Acetone and Isopropyl Alcohol were dispensedat weight ratio of 40/60 into a stainless steel container and stirredusing a stir bar. While stirring, the enteric copolymer Eudragit® L100and TEC were slowly added into the vortex of the mixed solvent. Mixingcontinued until the enteric copolymer completed dissolved. Whilestirring, Talc was slowly dispersed into the vortex of the solution.Mixing continued until the material was completely dispersed. Thesuspension was stirred throughout the coating process. The spray pumpwas calibrated to the target coating spray rate (8 g/min) using thesolution. The core beads were coated using Glatt GPCG 1 equipped with aWurster insert at Inlet air temperature of 35±10° C., Atomization airpressure of 1.5 bars and Wurster partition height of 15-30 mm. Duringcoating, the inlet air temperature, exhaust flap, and spray rate wereadjusted to maintain the exhaust air temperature between 27±5° C. Afterthe target amount of coating solution was sprayed, the coated beads weredried at an inlet air temperature of 40° C. for 20 minutes. The driedbeads were passed through a mechanical sieve (Vibroscreen) equipped witha pan at the bottom and a 14-MG mesh screen at the top. The beads thatpassed through the 14-MG mesh screen were collected and the oversizedbeads were rejected.

Encapsulation

The required amounts of the Component I and Component II Beads and Talcwere dispensed. For formulation IPX203-C0026, also Entacapone componentbeads were also dispensed. Talc was weighed at the weight ratio ofbeads/Talc at 99/1, and Component II beads and Talc were blendedthoroughly. For IPX203-C0026 product, Talc was also weighed at theweight ratio of ENT beads/Talc at 99/1, and Entacapone beads and Talcwere blended thoroughly. The Component I granules and Component II beads(from encapsulation section) were encapsulated into size 00 hard gelatincapsules, using MG Flexalab Encapsulator at the target fill weight forIPX203 products IPX203-C0023, -C0024, and -C0025. The Component Igranules, Component II beads (from encapsulation section), andentacapone beads (from encapsulation section) were encapsulated intosize 00 hard gelatin capsules, using MG Flexalab Encapsulator at thetarget fill weight for IPX203 products IPX203-C0026.

III. In Vitro LD Release Profiles of Four Formulations forPharmacokinetic Study (IPX203-B14-01)

The in vitro release profiles of IPX203-C0023, -C0024, -C0025 and -C0026were measured using USP 1 dissolution method at agitation speed of 75rpm in Simulated Gastric Fluid (pH 1.0, without enzyme) for first 2 hrsand followed by in Simulated Gastric Fluid (pH 7.0, without enzyme).FIG. 6 shows the release profiles of these four formulations.Formulation IPX203-C0025 and IPX203-C0026 contain the same Component IIbeads thus having same dissolution profiles. The T90 (time duration for90% of LD released) is approximately 4 hr, 5h and 7hrs for -C0023, -C0025 and -C0026, and -C0024, respectively.

IV. In vivo Evaluation (Biostudy IPX203-B14-01)

The in vivo performance of the prepared products IPX203-C0023, -C0024,-C0025, and -C0026 has been evaluated in 19 healthy volunteers in arelative bioavailability study IPX203-B14-01. IPX203-B14-01 was asingle-center, open-label, randomized, single-dose, five-sequence,five-treatment crossover study. During each treatment period, subjectsreceived a single dose of the assigned study treatment. There was aminimum 5-day washout between treatments. Blood samples were obtainedpredose and following dosing for approximately 12 hours for measurementof plasma concentrations. Thirty healthy male and female subjects, 18 to45 years of age at the time of dosing with a body mass index of 18.0 to30.0 kg/m², inclusive, were enrolled. All treatments were administeredwith 240 mL of room-temperature water to subjects in a fasted state.Subjects were instructed to swallow the study drugs intact withoutcrushing or chewing. FIG. 7 shows the levodopa plasma profiles for allthese regimens, and Table 15 shows the PK parameters relative toStalevo®.

TABLE 15 PK Parameters For All the Regimens Tested in IPX203 B13-01Study (n = 19) % of IPX203 % of IPX203 Test Test Formulation/Formulation/Staleyo ® Staleyo ® (normalized by LD dose) FormulationAUG_(0-∞) Cmax AUG_(0-∞) Cmax IPX203-C0023 277.3 179.4 77.0 49.8IPX203-C0024 199.1 121.4 55.3 33.7 IPX203-C0025 266.9 134.0 63.0 37.2IPX203-C0026 265.9 141.6 73.9 39.3

Table 16 shows the duration of time above 50% Cmax for IPX203-C0023,-C0024, -C0025, and -C0026 and conventional formulations.

TABLE 16 Duration of Time Above 50% Cmax IPX203-C0023, -C0024, -C0025,and -C0026 and Conventional Formulations % Coefficient of VariationFormulations N Median Mean (SD/Mean) IPX203-C0023 19 4.00 4.14 29.88IPX203-C0024 19 5.38 4.84 35.94 IPX203-C0025 19 5.38 5.20 29.30IPX203-C0026 19 4.88 5.23 36.32 C_(max) Values normalized to allowcomparison

Comparison of the LD plasma concentration profile of the testedformulations to the reference product Stalevo® indicates that: (1) theIPX203 regimens, based on IPX203-C0023, -C0024, -C 0025, and -C0026formulations, showed more extended effect than Stalevo® (Table 16 andFIG. 7 ); in addition, the IPX203 formulations showed more extendedeffect than Sinemet® or Sinemet® CR (Table 16 and FIG. 3 ; for Sinemet®CR (N=11), T>50% C_(max) is ˜3.41 hrs); (2) the IPX203 formulations;namely IPX203-C0023, -C0024, -C0025, and -C0026 formulations, showedrelatively flat plasma profiles for LD compared to Stalevo® (FIG. 7 );(3) the time duration between 50% of C_(max) to C_(max) forIPX203-C0023, -C0024, -C0025, and -C0026 formulations are much longerthan Stalevo®, (approximately 4.1-5.2 hrs for test formulations,compared to 2.3 hrs for Stalevo®); and (4) the variation of the timeduration between 50% C_(max) to C_(max) for IPX203-C0023, -C0024,-C0025, and -C0026 formulations is less than Stalevo®.

Example 6

Immediate release granules with the following composition were prepared:

Wt % Carbidopa USP* 46.20 Levodopa USP 42.80 Croscarmellose Sodium(AC-DI-SOL ®)  7.00 Povidone, USP (Plasdone K-29/32)  3.00 MagnesiumStearate  1.00 *monohydrate

The granules were prepared mixing using the procedure similar to thatdescribed above in Example 5, preparation of Component 1. Generally, theCD, LD and croscarmellose sodium were mixed in a high shear granulatorand wet granulated with a 5 wt % aqueous solution of povidone. Aftergranulation, the wet granules were passed through a Comil with a 0.375inch screen and dried in a fluidized bed. The dried granules were milledwith a Fitzmill equipped with a 30 mesh screen then blended withmagnesium stearate.

Example 7

Controlled release particles (beads) with the following composition wereprepared:

Wt % Core Levodopa USP 61.84 Microcrystalline Cellulose, NF  8.36(Avicel PH-101) Mannitol, USP (Mannogern  8.36 TM 2080 Granular) SodiumLauryl Sulfate  4.18 Povidone  0.84 Controlled Release Coat Celluloseacetate, NF (CA-398-10-NF)  1.88 Copovidone, NF (Kollidon VA64)  2.30Muco-Adhesive Coating Amino-Methacrylic Acid Copolymer, NF  6.38(EUDRAGIT E100) Talc  0.64 Enteric Coating Methacrylic Acid Copolymer,Type A, NF  3.31 (EUDRAGIT L100) Triethyl Citrate, NF  0.95 Talc, UPS 0.47 Blend Talc  0.50

The controlled release beads were prepared by a process similar to thatdescribed in Example 5, Preparation of Component II. Generally, the LD,microcrystalline cellulose, mannitol, and sodium lauryl sulfate weremixed in a high shear granulator and wet granulated with a 5 wt %aqueous solution of povidone. After granulation, the wet granules wereextruded using an extruder equipped with a 0.9 mm hole size screen andthe extrudate collected and loaded into a spheronizer equipped with a 3mm cross hatch disc. The wet spheronized beads were dried in a fluidizedbed drier. The dried beads were sieved through 16 MG and 24 MG meshscreens and the beads passing through the 16 MG screen but remaining onthe 24 MG screen were collected.

The collected beads were coated with a solution comprising celluloseacetate, copovidone, acetone and isopropyl alcohol using a fluidized bedcoating apparatus. After the target coating solution was applied, thecontrolled release coated beads were dried in the fluidized bed. Thedried controlled release beads were sieved through 14 MG and 24 MG meshscreens and the beads remaining on the 24 MG screen were collected. Thecollected controlled release coated beads were coated with amuco-adhesive solution comprising Eudragit E100, talc, acetone andisopropyl alcohol in the fluidized bed. After the target muco-adhesivecoating solution was applied to the controlled release coated beads, themuco-adhesive coated beads were dried in the fluidized bed. The driedmuco-adhesive coated beads were coated with an enteric coating solutioncomprising Eudragit L 100, talc triethyl citrate, acetone and isopropylalcohol in a fluidized bed. After the target enteric coating solutionwas applied to the muco-adhesive coated beads, the enteric coated beadswere dried in the fluidized bed. The dried enteric coated beads weresieved through 14 MG and 24 MG mesh screens and the beads remaining onthe 24 MG screen were collected. The collected beads were blended withtalc.

Example 8

The immediate release component of Example 6 and the controlled releasebeads of Example 7 were blended to create a mixture with 67.49 wt %controlled release beads and 32.51% immediate release granules. Themixture was filled into hard gelatin capsules containing (a) 180 mg LDand 45 mg CD and (b) 270 mg LD and 67.5 mg CD. The CD weight is based onCD anhydrous.

Example 9

Controlled release particles (beads) with the following composition wereprepared according to the procedure of Example 7:

Wt % Core Levodopa USP 60.12 Microcrystalline Cellulose, NF  8.12(Avicel PH-101) Mannitol, USP (Mannogern  8.12 TM 2080 Granular) SodiumLauryl Sulfate  4.06 Povidone  0.80 Controlled Release Coat Celluloseacetate, NF (CA-398-10-NF)  2.92 Copovidone, NF (Kollidon VA64)  3.57Muco-Adhesive Coating Amino-Methacrylic Acid Copolymer, NF  6.38(EUDRAGIT E100) Talc  0.64 Enteric Coating Methacrylic Acid Copolymer,Type A, NF  3.32 (EUDRAGIT L100) Triethyl Citrate, NF  0.95 Talc, UPS 0.47 Blend Talc  0.50

Example 10

The immediate release component of Example 6 and the controlled releasebeads of Example 9 were blended to create a mixture with 68.11 wt %controlled release beads and 31.89% immediate release granules. Themixture was filled into hard gelatin capsules containing (a) 180 mg LDand 45 mg CD and (b) 270 mg LD and 67.5 mg CD. The CD weight is based onCD anhydrous.

Example 11

Controlled release particles (beads) with the following composition wereprepared according to the procedure of Example 7:

Wt % Core Levodopa USP 61.83 Microcrystalline Cellulose, NF  8.36(Avicel PH-101) Mannitol, USP (Mannogern  8.36 TM 2080 Granular) SodiumLauryl Sulfate  4.18 Povidone  0.84 Controlled Release Coat Celluloseacetate, NF (CA-398-10-NF)  1.88 Copovidone, NF (Kollidon VA64)  2.30Muco-Adhesive Coating Amino-Methacrylic Acid Copolymer, NF  6.38(EUDRAGIT E100) Talc  0.64 Enteric Coating Methacrylic Acid Copolymer,Type A, NF  3.31 (EUDRAGIT L100) Triethyl Citrate, NF  0.95 Talc, UPS 0.47 Blend Talc  0.50

Example 12

The immediate release component of Example 6 and the controlled releasebeads of Example 11 were blended to create a mixture with 67.5 wt %controlled release beads and 32.5% immediate release granules. Themixture was filled into hard gelatin capsules containing (a) 140 mg LDand 35 mg CD; (b) 210 mg LD and 52.5 mg CD; (c) 280 mg LD and 70 mg CD;and (d) 350 mg LD and 87.5 mg CD. The CD weight is based on CDanhydrous. These dosage forms contained approximately 25% of the totalLD content in the immediate release component; 75% of the total LDcontent in the controlled release component and 100% of the total CDcontent in the immediate release component.

The 210 mg LD and 52.5 mg CD; 280 mg LD and 70 mg CD; and 350 mg LD and87.5 mg CD capsules prepared in this Example were tested using a USPType I apparatus, at 37° C.±0.5° C., with a rotational speed of 75 rpmsand 900 ml of simulated gastric fluid for 2 hours and pH 6.8 phosphatebuffer thereafter. The 140 mg LD and 35 mg CD capsules prepared in thisExample were tested using a USP Type I apparatus, at 37° C.±0.5° C.,with a rotational speed of 75 rpms and 900 ml of simulated gastric fluidfor 2 hours and pH 6.8 phosphate buffer thereafter. The results of thein vitro dissolution testing were as follows:

Time 140/35 mg 210/52.5 mg 280/70 mg 350/87.5 mg (hour) CD LD CD LD CDLD CD LD acid 0.5 103 28 103 29 103 29 103 29 2 103 40 103 41 103 42 10342 buffer 3 68 61 63 67 4 85 80 81 86 5 94 90 92 95 7 97 96 97 99 8 9797 98 100 10 97 99 98 100

The invention illustratively described herein suitably may be practicedin the absence of any element or elements, limitation or limitationswhich is not specifically disclosed herein. Thus, for example, in eachinstance herein, any of the terms “comprising,” “consisting essentiallyof” and “consisting of” may be replaced with either of the other twoterms. The terms and expressions which have been employed are used asterms of description and not of limitation, and there is no intention inthe use of such terms and expressions of excluding any equivalents ofthe features shown and described or portions thereof, but it isrecognized that various modifications are possible within the scope ofthe invention claimed. Thus, it should be understood that although thepresent invention has been specifically disclosed by preferredembodiments and optional features, modification and variation of theconcepts herein disclosed may be resorted to by those skilled in theart, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the appended claims.

What is claimed is:
 1. A multiparticulate controlled release formulationcomprising: (a) a controlled release component comprising a plurality ofcontrolled release particles comprising a core comprising levodopa orlevodopa equivalence, a mucoadhesive layer or coat surrounding the core;and an enteric coat or layer surrounding the mucoadhesive layer or coat,wherein mucoadhesive layer or coat comprises a cationic mucoadhesivepolymer; and (b) an immediate release component comprising levodopa andcarbidopa.
 2. The multiparticulate controlled release formulation ofclaim 1, wherein the core of the controlled release component is aspheronized core.
 3. The multiparticulate controlled release formulationof claim 2, wherein the spheronized core is a spheronized bead.
 4. Themultiparticulate controlled release formulation of claim 1, wherein thecore of the controlled release component is an extruded and spheronizedcore.
 5. The multiparticulate controlled release formulation of claim 1,wherein the cationic mucoadhesive polymer is an aminoalkyl methacrylatecopolymer.
 6. The multiparticulate controlled release formulation ofclaim 1, wherein the cationic mucoadhesive copolymer is poly(butylmethacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methylmethacrylate) (1:2:1).
 7. The multiparticulate controlled releaseformulation of claim 1, wherein the controlled release component passesthrough a mesh screen size of 16 or less and is retained on a meshscreen size of at least
 18. 8. The multiparticulate formulation of claim1, wherein the controlled release component passes through a mesh screensize of 16 or less and is retained on a mesh screen size of
 24. 9. Themultiparticulate formulation of claim 1, wherein the controlled releasecomponent passes through a mesh screen size of 12 and is retained on amesh screen size of
 24. 10. The multiparticulate controlled releaseformulation of claim 1, wherein the controlled release componentreleases less than 20% of the levodopa within two hours, measured usinga United States Pharmacopeia (USP) Type I apparatus at 75 rpm, in about900 ml of a dissolution medium at pH of about
 1. 11. Themultiparticulate formulation of claim 1, wherein the formulationreleases from about 75% to about 100% of the carbidopa in 30 minutes orless, measured using United States Pharmacopeia (USP) Type I or Type IIapparatus, in about 500-900 mL of an aqueous medium with a pH from about1 to about 7.5.
 12. The multiparticulate controlled release formulationof claim 1, wherein the formulation releases from about 85% to about100% of the carbidopa in 30 minutes or less, measured using USP Type Ior Type II apparatus, in about 500-900 mL of an aqueous medium with a pHfrom about 1 to about 7.5.
 13. The multiparticulate controlled releaseformulation of claim 1, further comprising a rate-controlling coat orlayer which undercoats the mucoadhesive layer or coat within thecontrolled release particles.
 14. The multiparticulate controlledrelease formulation of claim 13, wherein the rate-controlling coat orlayer comprises ethylcellulose or cellulose acetate.
 15. Themultiparticulate controlled release formulation of claim 1, wherein theimmediate release component (b) is formulated as a granule.
 16. Themultiparticulate controlled release formulation of claim 1, wherein theformulation is encapsulated in a capsule.
 17. The multiparticulatecontrolled release formulation of claim 1, wherein the enteric coat orlayer comprises one or more methacrylic acid copolymers.
 18. Amultiparticulate controlled release formulation comprising a pluralityof controlled release particles comprising a spheronized core comprisinglevodopa or levodopa equivalence; a mucoadhesive layer or coatsurrounding the core; and an enteric coat or surrounding themucoadhesive layer or coat.
 19. The multiparticulate controlled releaseformulation of claim 18, wherein the spheronized core is a spheronizedbead.
 20. The multiparticulate controlled release formulation of claim19, wherein the spheronized bead passes through a mesh screen size of 12and is retained on a mesh screen size of
 24. 21. The multiparticulatecontrolled release formulation of claim 18, wherein the mucoadhesivelayer or coat comprises a cationic mucoadhesive polymer.
 22. Themultiparticulate controlled release formulation of claim 21, wherein thecationic mucoadhesive polymer is poly(butylmethacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methylmethacrylate) (1:2:1).
 23. The multiparticulate controlled releaseformulation of claim 18, further comprising a rate-controlling coat orlayer which undercoats the mucoadhesive layer or coat within thecontrolled release particles.
 24. The multiparticulate controlledrelease formulation of claim 23, wherein the rate-controlling coat orlayer comprises ethylcellulose or cellulose acetate.
 25. Themultiparticulate controlled release formulation of claim 18, wherein theformulation further comprises a plurality of immediate release particlescomprising levodopa or levodopa equivalence.
 26. The multiparticulatecontrolled release formulation of claim 25, wherein the immediaterelease particles further comprise carbidopa or carbidopa equivalence.27. The multiparticulate controlled release formulation of claim 25,wherein the immediate release particles are immediate release granules.28. A multiparticulate controlled release formulation comprising aplurality of controlled release particles comprising a core comprisinglevodopa or levodopa equivalence; a mucoadhesive layer or coatsurrounding the core; and an enteric coat or surrounding themucoadhesive layer or coat, wherein the formulation comprises from 90 mgto 500 mg of levodopa or levodopa equivalence.
 29. The multiparticulatecontrolled release formulation of claim 28, wherein the formulationfurther comprises a plurality of immediate release particles.